N-aroyl cyclic amine derivatives as orexin receptor antagonists

ABSTRACT

Disclosed are N-aroyl cyclic amine derivatives having the formula: 
                         
where the variables are as define herein, and their use as pharmaceuticals, specifically as orexin receptor antagonists.

This application is a continuation of application Ser. No. 10/481,133,filed Apr. 26, 2004, now U.S. Pat. No. 7,470,710, which is a 371 ofInternational Application No. PCT/EP02/07009, filed 25 Jun. 2002, whichclaims the priority of GB 0130342.9, filed 19 Dec. 2001, and GB0115863.3, filed 28 Jun. 2001, which are incorporated herein in theirentireties.

This invention relates to N-aroyl cyclic amine derivatives and their useas pharmaceuticals.

Many medically significant biological processes are mediated by proteinsparticipating in signal transduction pathways that involve G-proteinsand/or second messengers.

Polypeptides and polynucleotides encoding the human 7-transmembraneG-protein coupled neuropeptide receptor, orexin-1 (HFGAN72), have beenidentified and are disclosed in EP-A-875565, EP-A-875566 and WO96/34877. Polypeptides and polynucleotides encoding a second humanorexin receptor, orexin-2 (HFGANP), have been identified and aredisclosed in EP-A-893498.

Polypeptides and polynucleotides encoding polypeptides which are ligandsfor the orexin-1 receptor, e.g. orexin-A (Lig72A) are disclosed inEP-A-849361.

Orexin receptors are found in the mammalian host and may be responsiblefor many biological functions, including pathologies including, but notlimited to, depression; anxiety; addictions; obsessive compulsivedisorder; affective neurosis/disorder; depressive neurosis/disorder;anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder;sexual dysfunction; psychosexual dysfunction; sex disorder; sexualdisorder; schizophrenia; manic depression; delerium; dementia; severemental retardation and dyskinesias such as Huntington's disease andGilles de la Tourett's syndrome; disturbed biological and circadianrhythms; feeding disorders, such as anorexia, bulimia, cachexia, andobesity; diabetes; appetite/taste disorders; vomiting/nausea; asthma;cancer; Parkinson's disease; Cushing's syndrome/disease; basophiladenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysistumor/adenoma; hypothalamic diseases; Froehlich's syndrome;adrenohypophysis disease; hypophysis disease; hypophysis tumor/adenoma;pituitary growth hormone; adrenohypophysis hypofunction;adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman'ssyndrome (anosmia, hyposmia); functional or psychogenic amenorrhea;hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenaldysfunction; idiopathic hyperprolactinemia; hypothalamic disorders ofgrowth hormone deficiency; idiopathic growth hormone deficiency;dwarfism; gigantism; acromegaly; and sleep disturbances associated withsuch diseases as neurological disorders, neuropathic pain and restlessleg syndrome, heart and lung diseases; acute and congestive heartfailure; hypotension; hypertension; urinary retention; osteoporosis;angina pectoris; myocardial infarction; ischaemic or haemorrhagicstroke; subarachnoid haemorrhage; head injury such as sub-arachnoidhaemorrhage associated with traumatic head injury; ulcers; allergies;benign prostatic hypertrophy; chronic renal failure; renal disease;impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced orexaggerated sensitivity to pain, such as hyperalgesia, causalgia andallodynia; acute pain; burn pain; atypical facial pain; neuropathicpain; back pain; complex regional pain syndromes I and II; arthriticpain; sports injury pain; pain related to infection, e.g. HIV,post-polio syndrome, and post-herpetic neuralgia; phantom limb pain;labour pain; cancer pain; post-chemotherapy pain; post-stroke pain;post-operative pain; neuralgia; nausea, vomiting; conditions associatedwith visceral pain including irritable bowel syndrome, migraine andangina; urinary bladder incontinence e.g. urge incontinence; toleranceto narcotics or withdrawal from narcotics; sleep disorders; sleep apnea;narcolepsy; insomnia; parasomnia; jet-lag syndrome; andneurodegenerative disorders, which includes nosological entities such asdisinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration, epilepsy, and seizure disorders.

Experiments have shown that central administration of the ligandorexin-A (described in more detail below) stimulated food intake infreely-feeding rats during a 4 hour time period. This increase wasapproximately four-fold over control rats receiving vehicle. These datasuggest that orexin-A may be an endogenous regulator of appetite.Therefore, antagonists of its receptor may be useful in the treatment ofobesity and diabetes, see Cell, 1998, 92, 573-585.

There is a significant incidence of obesity in westernised societies.According to WHO definitions a mean of 35% of subjects in 39 studieswere overweight and a further 22% clinically obese. It has beenestimated that 5.7% of all healthcare costs in the USA are a consequenceof obesity. About 85% of Type 2 diabetics are obese, and diet andexercise are of value in all diabetics. The incidence of diagnoseddiabetes in westernised countries is typically 5% and there areestimated to be an equal number undiagnosed. The incidence of bothdiseases is rising, demonstrating the inadequacy of current treatmentswhich may be either ineffective or have toxicity risks includingcardiovascular effects. Treatment of diabetes with sulfonylureas orinsulin can cause hypoglycemia, whilst metformin causes GI side-effects.No drug treatment for Type 2 diabetes has been shown to reduce thelong-term complications of the disease. Insulin sensitisers will beuseful for many diabetics, however they do not have an anti-obesityeffect.

Rat sleep/EEG studies have also shown that central administration oforexin-A, an agonist of the orexin receptors, causes a dose-relatedincrease in arousal, largely at the expense of a reduction inparadoxical sleep and slow wave sleep 2, when administered at the onsetof the normal sleep period. Therefore antagonists of its receptor may beuseful in the treatment of sleep disorders including insomnia.

The present invention provides N-aroyl cyclic amine derivatives whichare non-peptide antagonists of human orexin receptors, in particularorexin-1 receptors. In particular, these compounds are of potential usein the treatment of obesity, including obesity observed in Type 2(non-insulin-dependent) diabetes patients, and/or sleep disordersAdditionally these compounds are useful in stroke, particularly ischemicor haemorrhagic stroke, and/or blocking the emetic response i.e. thecompounds are useful in the treatment of nausea and vomiting.

International Patent Applications WO99/09024, WO99/58533, WO00/47577 andWO00/47580 disclose phenyl urea derivatives and WO00/47576 disclosesquinolinyl cinnamide derivatives as orexin receptor antagonists.(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazineis disclosed in EP899270 as a starting material in the preparation ofcompounds useful for therapy of functional and inflammatory disorders ofthe gastrointestinal tract. The compound is also disclosed as Example 6in EP655442. EP655442 describes piperizine derivatives useful asTachykinin antagonists. 1-Benzoyl-2-[(1H-indol-3-yl)methyl]piperazine isalso disclosed therein.

(2R)-1-(3,5-dichlorobenzoyl)-2-[(1H-indol-3-yl)methyl]piperazine and(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[1H-indol-3-yl)methyl]piperazineare used as starting materials/intermediates in WO9857954.

(2R)-2-[1H-indol-3-yl)methyl]-1-[3-methoxy-5-trifluoromethyl)benzoyl]piperazine,is disclosed as a prepared by preparation 42 in WO00/35915.

According to the invention there is provided a compound of formula (I):

wherein:

X represents a bond, oxygen, NR³ or a group (CH₂)_(n), wherein nrepresents 1, 2 or 3;

Y represents CH₂, CO, CH(OH), or CH₂CH(OH);

Het is an optionally substituted bicyclic heteroaryl group containing upto 4 heteroatoms selected from N, O and S;

Ar² represents an optionally substituted phenyl or a 5- or 6-memberedheterocyclyl group containing up to 3 heteroatoms selected from N, O andS, wherein the phenyl or heterocyclyl group is substituted by R¹ andfurther optional substituents; or Ar² represents an optionallysubstituted bicyclic aromatic or bicyclic heteroaromatic groupcontaining up to 3 heteroatoms selected from N, O and S;

R¹ represents hydrogen, optionally substituted (C₁₋₄)alkoxy, halo,cyano, optionally substituted (C₁₋₆)alkyl, optionally substitutedphenyl, or an optionally substituted 5- or 6-membered heterocyclyl groupcontaining up to 4 heteroatoms selected from N, O and S;

R³ represents hydrogen or an optionally substituent (C₁₋₄)alkyl otherthan when Het is indolyl where R³ represents hydrogen or (C₁₋₄) alkyl;

or a pharmaceutically acceptable salt thereof.

with the proviso that;

when X is NH, Y is CH₂ and Het is indolyl, Ar² is not3,5-bis(trifluoromethyl)phenyl;

or the compound is not

(2R)-1-(3,5-dichlorobenzoyl)-2-[(1H-indol-3-yl)methyl]piperazine;

(2R)-2-[1H-indol-3-yl)methyl]-1-[3-methoxy-5-trifluoromethyl)benzoyl]piperazine;or

1-benzolyl-2-[1H-indol-3-yl)methyl]piperazine.

Preferably where Ar² represents phenyl or a 5- or 6-memberedheterocyclyl group containing up to 3 heteroatoms selected from N, O andS, the R¹ group is situated adjacent to the point of attachment to theamide carbonyl.

X is preferably a bond, oxygen or CH₂, NH or NMe, more preferably CH₂,NH or NMe, most preferably CH₂.

Alternatively X is preferably a bond, oxygen or (CH₂)_(n) wherein n is 1or 2.

Y is preferably CH₂.

Preferably R³ is hydrogen or a (C₁₋₄)alkyl.

Het may have up to 5, preferably 1, 2 or 3 optional substituents.

Examples of when Het is an optionally substituted bicyclic heteroarylgroup are quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl,benzothienyl, benzofuranyl, benzimidazolyl, naphthyridinyl orbenzothiazolyl. Additionally Het may be indolyl, triazolopyridinyl,furopyridinyl, pyridopyrimidinyl, isoquinolinyl or quinolinyl.Furthermore Het can be oxazolylpyridinyl or tetrahydrobenzimidazolyl,tetrahydrobenzofuranyl, or tetrahydrotriazolopyridinyl.

Preferably Het is benzofuranyl, benzoxazolyl, benzimidazolyl,furopyridinyl, benzothiazolyl, indolyl, benzothienyl, triazolopyridinyl,quinolinyl and tetrahydrotriazolopyryidinyl, more preferablybenzimidazolyl, benzofuranyl, benzoxazolyl, even more preferablybenzofuranyl or benzimidazolyl.

When Ar² is a 5- or 6-membered heteroaryl group containing up to 3heteroatoms selected from N, O and S, it may be furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,triazolyl, triazinyl, pyridazinyl, pyridinyl, pyrimidinyl, isothiazolyl,isoxazolyl, pyrazinyl or pyrazolyl.

More specifically, examples of Ar² are thiazolyl, pyrazolyl, triazolyl,pyridazinyl, oxazolyl, pyridinyl, pyrimidinyl, isoxazolyl and thienyl.

When R¹ is a 5- or 6-membered heterocyclyl group containing up to 4heteroatoms selected from N, O and S, it may be furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,pyridinyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl,isoxazolyl, pyrazinyl or pyrazolyl. Additional heterocyclyl groups canbe morpholinyl, piperazinyl and thiomorpholinyl. Furthermore it can betetrazolyl, piperidinyl or pyrrolidinyl.

Preferably when R¹ is a 5- or 6-membered heterocyclyl group containingup to 4 heteroatoms selected from N, O and S, it may be oxadiazolyl,pyridinyl, pyrimidinyl, morpholinyl pyrazolyl or pyrrolyl.

Examples of where Ar² represents an optionally substituted bicyclicaromatic or bicyclic heteroaromatic include naphthyl, quinolinyl,napththyridinyl, benzofuranyl, benzimidazolyl, quinoxalinyl orquinazolinyl. Additionally Ar² may be isoquinolinyl or benzoxazolyl.Furthermore it can benzotriazolyl, benzothienyl, indolyl,benzothiazolyl, or benzothiadiazolyl.

Preferably Ar² represents optionally substituted phenyl, pyridinyl,thiazolyl, pyrazolyl, pyridazinyl, thienyl, naphthyl, triazolyl,isoxazolyl, quinolinyl, or isoquinolinyl.

More preferably Ar² represents optionally substituted phenyl, pyridinyl,thiazolyl, pyrazolyl, thienyl, triazolyl, quinolinyl, or isoquinolinyl.

Even more preferably Ar² represents optionally substituted phenyl,pyridinyl, thiazolyl, pyrazolyl, thienyl, or 1,2,3-triazolyl.

Alternatively R¹ represents hydrogen, optionally substituted(C₁₋₄)alkoxy, halo, optionally substituted (C₁₋₆)alkyl, optionallysubstituted phenyl, or an optionally substituted 5- or 6-memberedheterocyclyl group containing up to 3 heteroatoms selected from N, O andS.

Preferably R¹ represents optionally substituted (C₁₋₄)alkoxy, halo,optionally substituted (C₁₋₆)alkyl, optionally substituted phenyl, or anoptionally substituted 5- or 6-membered heterocyclyl group containing upto 3 heteroatoms selected from N, O and S.

Even more preferably R¹ represents an optionally substituted phenyl,pyridinyl, pyrazolyl pyrimidinyl or oxadiazolyl group.

Optional substituents for the groups Het, Ar², R¹ and R³ includehalogen, hydroxy, oxo, cyano, nitro, (C₁₋₄)alkyl, (C₁₋₄)alkoxy,hydroxy(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkoxy, halo(C₁₋₄)alkyl,halo(C₁₋₄)alkoxy, aryl(C₁₋₄)alkoxy, (C₁₋₄)alkylthio, hydroxy(C₁₋₄)alkyl,(C₁₋₄)alkoxy(C₁₋₄)alkyl, (C₃₋₆)cycloalkyl(C₁₋₄)alkoxy, (C₁₋₄)alkanoyl,(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylsulfonyl, (C₁₋₄)alkylsulfonyloxy,(C₁₋₄)alkylsulfonyl(C₁₋₄)alkyl, arylsulfonyl, arylsulfonyloxy,arylsulfonyl(C₁₋₄)alkyl, (C₁₋₄)alkylsulfonamido, (C₁₋₄)alkylamido,(C₁₋₄)alkylsulfonamido(C₁₋₄)alkyl, (C₁₋₄)alkylamido(C₁₋₄)alkyl,arylsulfonamido, arylcarboxamido, arylsulfonamido(C₁₋₄)alkyl,arylcarboxamido(C₁₋₄)alkyl, aroyl, aroyl(C₁₋₄)alkyl, oraryl(C₁₋₄)alkanoyl group; a group R^(a)R^(b)N—, R^(a)OCO(CH₂)_(r),R^(a)CON(R^(a))(CH₂)_(r), R^(a)R^(b)NCO(CH₂)_(r),R^(a)R^(b)NSO₂(CH₂)_(r) or R^(a)SO₂NR^(b)(CH₂)_(r) where each of R^(a)and R^(b) independently represents a hydrogen atom or a (C₁₋₄)alkylgroup or where appropriate R^(a)R^(b) forms part of a(C₃₋₆)azacyloalkane or (C₃₋₆)(2-oxo)azacycloalkane ring and r representszero or an integer from 1 to 4. Additional substituents are (C₁₋₄)acyl,aryl, aryl(C₁₋₄)alkyl, (C₁₋₄)alkylamino(C₁₋₄)alkyl, R^(a)R^(b)N(CH₂)n-,R^(a)R^(b)N(CH₂)nO—, wherein n represents an integer from 1 to 4.Additionally when the substituent is R^(a)R^(b)N(CH₂)n- orR^(a)R^(b)N(CH₂)nO, R^(a) with at least one CH₂ of the (CH₂)n portion ofthe group form a (C₃₋₆)azacycloalkane and R^(b) represents hydrogen, a(C₁₋₄)alkyl group or with the nitrogen to which it is attached forms asecond (C₃₋₆)azacycloalkane fused to the first (C₃₋₆)azacycloalkane.

Preferred optional substituents for Ar² are halogen, cyano, (C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, (C₁₋₄)alkoxy(C₁₋₄)alkyl, R^(a)R^(b)N(CH₂)n orR^(a)R^(b)N, more preferably halogen, cyano and (C₁₋₄)alkyl. Additionalsubstituents are (C₁₋₄)acyl, R^(a)R^(b)N(CH₂)nO, (C₁₋₄)alkoxy, phenyl,and (C₁₋₄)alkylamido.

More preferred substituents for Ar² are (C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl,R^(a)R^(b)N, (C₁₋₄)alkoxy, R^(a)R^(b)N(CH₂)n, (C₁₋₄)acyl, and(C₁₋₄)alkylamido.

Preferred optional substituents for Het are halogen, cyano, (C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, (C₁₋₄)acyl, (C₁₋₄)alkoxy(C₁₋₄)alkyl,R^(a)R^(b)NCO(CH₂)_(r), R^(a)R^(b)N(CH₂)n, R^(a)R^(b)N(CH₂)nO orR^(a)R^(b)N. Additional optional substituents are (C₁₋₄)alkoxy or CF₃.

More preferred substituents for Het are halogen, R^(a)R^(b)NCO(CH₂)_(r),cyano, (C₁₋₄)alkoxy, (C₁₋₄)alkyl, R^(a)R^(b)N(CH₂)n, hydroxy(C₁₋₄)alkyl,(C₁₋₄)acyl or (C₁₋₄)alkoxy(C₁₋₄)alkyl.

Preferred optional substituents for R¹ are halogen,(C₁₋₄)alkoxy(C₁₋₄)alkyl, R^(a)R^(b)N, R^(a)R^(b)N(CH₂)nO orR^(a)R^(b)N(CH₂)n. Additional optional substituents are (C₁₋₄)alkyl,(C₁₋₄)alkoxy and (C₁₋₄)acyl.

More preferred substituents for R¹ are halogen, R^(a)R^(b)N(CH₂)nO,(C₁₋₄)alkyl, and (C₁₋₄)alkoxy.

Preferred optional substituents for R³ may be selected from halogen,hydroxy, cyano, (C₁₋₄)alkoxy, R^(a)R^(b)N(CH₂)nO or R^(a)R^(b)N.

-   -   In the groups Het and Ar², substituents positioned ortho to one        another may be linked to form a ring.

Illustrative compounds of formula (I) can be selected from:

1 (RS)-2-(2-Benzonaranylmethyl)-1-((5-(4-fluorophenyl)-2-methyl-thiazol-4-yl)-carbonyl)-piperidine 2(RS)-1-(2-Benzooxazol-2-ylmethyl-piperidin-1-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 3(RS)-1-(2-Benzooxazol-2-ylmethyl-piperidin-1-yl)-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanoneand pharmaceutical acceptable salts thereof.Additional compounds of formula (I) can be selected from:

4(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-[4-(4-fluoro-phenyl)-1-methyl-1-H-pyrazol-3-yl]-methane 5(RS)-1-[2-(5-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 6(RS)-1-[2-(5-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-(5-pyridin-2-yl-thiazol-4-yl)-methanone 7(RS)-1-[2-(5-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-quinolin-4-yl-methanone 8(RS)-1-[2-(5-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-quinolin-5-yl-methanone 9(RS)-1-[2-(5-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-(2-methoxy-pyridin-3-yl)-methanone 10(RS)-1-[2-Dimethylamino-5-(4-fluoro-phenyl)-thiazol-4-yl]-1-[2-(5-fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl]-methanone 11(RS)-1-[2-(5-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-(2-morpholin-4-yl-phenyl)-methanone 12(RS)-1-[2-(5-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy-phenyl)-methanone 13(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-[2-(2-dimethylamino-ethoxy)-phenyl]-methanone 14(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-quinolin-8-yl-methanone 15(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-(2-pyrimidin-2-yl-phenyl)-methanone 16(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-[5-(4-fluoro-phenyl)-2H-[1,2,3]triazol-4-yl]-methanone 17(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-[4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 18(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-[5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone 19(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-isoquinolin-8-yl-methanone 20(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-isoquinolin-5-yl-methanone 21 (RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-{5-[3-(3-dimethylamino-propoxy)-phenyl]-2-methyl-thiazol-4-yl}-methanone 22(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-{5-[3-(4-dimethylamino-butoxy)-phenyl]-2-methyl-thiazol-4-yl}-methanone 23(RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-(2-furo[2,3-b]pyridin-2-ylmethyl-piperidin-1-yl)-methanone 24(RS)-1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazole-3-yl]-(2-furo[2,3-b]pyridin-2-ylmethyl-piperidin-1-yl)methanone 25(RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-(2-quinolin-2-ylmethyl-piperidin-1-yl)-methanone 26(RS)-1-Benzofuran-2-yl-1-(1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-yl)-methanone 27(RS)-1-[2-(1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 28(RS)-1-[2-(5-Chloro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 29(RS)-1-[2-(5-Fluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 30(RS)-1-[2-(5-Chloro-6-fluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 31(RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(4-methyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-methanone 32(RS)-1-[2-(4,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 33(RS)-1-[2-(4-Dimethylaminomethyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone34 (RS)-1-[2-(5-Bromo-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 35(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 36(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 37(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone 38(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone 39(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 40(RS)-1-[2-(5-Methoxy-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 41(RS)-1-[2-(6,7-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-(2-methyl-5-phenyl-thiazol-4-yl)-methanone 42(RS)-1-[2-(6,7-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 43(RS)-1-[2-(6,7-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 44(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-{5-[3-(2-dimethylamino-ethoxy)-phenyl]-2-methyl-thiazol-4-yl}- methanone45(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 46(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 47(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy-phenyl)-methanone 48(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-(2-ethoxy-phenyl)-methanone 49(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-(2,6-dimethoxy-phenyl)-methanone 50(RS)-1-[2-(6,7-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-(2-pyrazol-1-yl-phenyl)-methanone 51(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 52(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl] -methanone 53(RS)-1-[2-(Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[1-(2-dimethylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanone54(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-2H-[1,2,3]triazol-4-yl]-methanone 55(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-{2-[3-(3-dimethylamino-propoxy)-phenyl]-thiophen-3-yl}-methanone 56(RS)-1-[2-(5,6-Difluoro-1-methyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone571-[(S)-2-(1H-Benzoimidazol-2-ylmethyl)-pyrrolidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 581-[(S)-2-(5,6-Difluoro-1H-Benzoimidazol-2-ylmethyl)-pyrrolidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 591-[(S)-2-(5,6-Difluoro-1H-Benzoimidazol-2-ylmethyl)-pyrrolidin-1-yl]-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]methanone 60(RS)-1-(2-Benzothiazol-2-ylmethylpiperidin-1-yl)-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]-methanone 61(RS)-1-(2-Benzothiazol-2-ylmethylpiperidin-1-yl)-1-[4-(4-fluorophenyl)-1-methyl-1-H-pyrazol-3-yl]-methanone 62(RS)-1-(2-Benzothiazol-2-ylmethylpiperidin-1-yl)-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)phenyl]-methanone 63(RS)-1-[5-(4-Fluorophenyl)-2-methylthiazol-4-yl]-1-[2-(5,6,7,8-tetrahydro-[1,2,4]-triazolo[1,5-a]pyridin-2-ylmethyl)-piperidin-1-yl]-methanone 64(RS)-1-[5-(4-Fluorophenyl)-2-methylthiazol-4-yl]-1-(2-[1,2,4]triazolo[1,5-a]pyridin-2-ylmethylpiperidin-1-yl)-methanone 651-[(RS)-2-((RS)-2-Benzofuran-2-yl-2-hydroxy-ethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone (as separatediastereoisomers) 66(RS)-1-[2-(4-Bromo-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone 67(RS)-1-[2-(4-Cyano-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone 68(RS)-1-[2-(4-Acetyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone 69(RS)-2-(1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-ylmethyl)-1H-benzoimidazole-5-carbonitrile 70(RS)-1-[2-(5,6-Difluoro-1-propyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 71(RS)-1-{2-[5,6-Difluoro-1-(2-methoxy-ethyl)-1H-benzoimidazol-2-ylmethyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 72(RS)-1-{2-[1-(2-Dimethylamino-ethyl)-5,6-difluoro-1H-benzoimidazol-2-ylmethyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 73(RS)-1-{2-[5,6-difluoro-1-(2-hydroxy-ethyl)-1H-benzoimidazol-2-ylmethyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 74(RS)-1-[2-(6,7-Difluoro-1-methyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methyl-thiazol-4-yl]-methanone75 (RS)-1-[2-(4,5-Difluoro-1-methyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methyl-thiazol-4-yl]-methanone76 (RS)-2-(1-{1-[5-(4-Fluorophenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-ylmethyl)-benzofuran-3-carboxylic acid amide 77(RS)-2-(1-{1-[4-(4-Fluorophenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-benzofuran-3-carboxylic acid amide 78(RS)-1-[3-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-morpholin-4-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 79(RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-(2-furo[3,2-b]-pyridin-2-ylmethyl-piperidin-1-yl)methanone 80(RS)-1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazole-3-yl)-(2-furo[3,2-b]pyridin-2-ylmethyl-piperidin-1-yl)methanone 81(RS)-1-[2-(3-Bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 82(RS)-2-(1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-ylmethyl)-benzofuran-3-carbonitrile 83(RS)-1-[2-(5-Fluorobenzoruran-2-ylmethyl)-4-methylpiperazin-1-yl]-1-[5-(4-fluorophenyl)-2-methythiazol-4-yl]methanone 84(RS)-1-(2-Benzofuran-2-ylmethyl-4-methyl-piperazin-1-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl)]-methanone 85(RS)-1-(2-Benzofuran-2-ylmethyl-piperazin-1-yl)-1-[5-(4-fluorophenyl)-2-methyl-thiazol-4-yl]-methanone 861-{(RS)-2-[(RS)-1-(5-Fluoro-benzofurany-2-yl)-1-hydroxy-methyl]-4-methyl-piperazin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 871-{(RS)-2-[(RS)-1-(5-Fluoro-benzofurany-2-yl)-1-hydroxy-methyl]-4-methyl-piperazin-1-yl}-1-(2-trifluoromethoxy-phenyl)-methanone 88(RS)-1-[2-(1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-ylmethyl)-benzofuran-3-yl]-ethanone 89(R)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone and(S)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoneand pharmaceutically acceptable salts thereof.Further compounds of formula (I) can be selected from

90 (RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-[5-(4-methoxy-phenyl)-2-methyl-thiazol-4-yl]-methanone 91(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-{5-[3-(2-dimethylamino-ethoxy)-phenyl]-2-methyl-thiazol-4-yl}-methanone 92(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-(5-methyl-3-phenyl-isoxazol-4-yl)-methanone 931-[3-(2,6-Dichloro-phenyl)-5-methyl-isoxazol-4-yl]-1-[2-(4,5-difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-methanone 94(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[4-(4-fluoro-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanone 95(RS)-1-[3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-1-[2-(4,5-difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-methanone 96(RS)-1-[3-(2-Chloro-phenyl)-5-methyl-isoxazol-4-yl]-1-[2-(4,5-difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-methanone 97(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-(2-propoxy-phenyl)-methanone 98(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-(2-isopropoxy-phenyl)-methanone 99(RS)-1-(2-Benzyloxy-phenyl)-1-[2-(4,5-difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-methanone 100(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-(2-ethoxy-6-methoxy-phenyl)-methanone 101(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-(2-ethoxy-6-methyl-phenyl)-methanone 102(RS)-1-(2,6-Diethoxy-phenyl)-1-[2-(4,5-difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-methanone 1031-(3-{1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-methanoyl}-4-ethoxy-phenyl)-ethanone 104(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-(2-ethoxy-naphthalen-1-yl)-methanone 105(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-(2-pyridin-2-yl-phenyl)-methanone 1061-[2-(6,7-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-(2-pyrrol-1-yl-phenyl)-methanone 107(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-{5-[3-(3-dimethylamino-propoxy)-phenyl]-2-methyl-thiazol-4-yl}-methanone 108(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-{5-[3-(4-dimethylamino-butoxy)-phenyl]-2-methyl-thiazol-4-yl}- methanone109(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methoxy-thiazol-4-yl]-methanone 110(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[2-ethyl-5-(4-fluoro-phenyl)-thiazol-4-yl]-methanone 111(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 112(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 113(RS)-1-[2-(4-Fluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 114(RS)-1-[2-(4-Fluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 115(RS)-1-[2-(4-Fluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 116(RS)-1-[2-(4-Fluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[4-(4-fluoro-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanone 117(RS)-1-(2-Ethoxy-phenyl)-1-[2-(4-fluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-methanone 118(RS)-1-[2-(4-Fluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone 119(RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{2-[4-(1-hydroxy-ethyl)-1H-benzoimidazol-2-ylmethyl]-piperidin-1-yl}-methanone 120(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-[5-(4-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone 121(RS)-1-[2-(3-Chloro-furo[3,2-b]pyridin-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 122(RS)-1-[2-(5,6-Difluoro-1-methyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone 123(RS)-1-[2-(5-Chloro-benzofuran-2-ylmethyl)-4-methyl-piperazin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 124(RS)-1-[2-(5-Chloro-benzofuran-2-ylmethyl)-piperazin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 125(RS)-1-[2-(5,7-Dichloro-benzofuran-2-ylmethyl)-4-methyl-piperazin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 126(RS)-1-[2-(5,7-Dichloro-benzofuran-2-ylmethyl)-piperazin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 127(RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(1H-indol-2-ylmethyl)-piperidin-1-yl]-methanone 128(RS)-5-[1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-methanoyl]-4H-benzo[1,4]oxazin-3-one 129(RS)-1-[2-(5-Bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 130(RS)-1-[2-(5-Cyano-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 131(RS)-1-[2-(4-Bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 132(RS)-1-[2-(4-Cyano-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 133(RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(3-methyl-benzofuran-2-ylmethyl)-piperidin-1-yl]-methanone 134(RS)-1-[2-(4-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 135(RS)-1-[2-(4-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 136(RS)-1-[2-(4,6-Dichloro-benzofuran-2-ylmethyl)-4-methyl-piperazin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 137(RS)-1-[2-(4,6-Dichloro-benzofuran-2-ylmethyl)-piperazin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 138(RS)-1-(2-Benzofuran-2-ylmethyl-pyrrolidin-1-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 139(RS)-1-(2-Benzofuran-2-ylmethyl-pyrrolidin-1-yl)-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 140(RS)-1-(2-Benzo[b]thiophen-2-ylmethyl-piperidin-1-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 141(RS)-1-(2-Benzo[b]thiophen-2-ylmethyl-piperidin-1-yl)-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 142(RS)-1-(2-Benzo[b]thiophen-2-ylmethyl-piperidin-1-yl)-1-quinolin-8-yl-methanone 143(RS)-1-(2-Benzoruran-2-ylmethyl-piperidin-1-yl)-1-(2-methyl-5-phenyl-thiazol-4-yl)-methanone 1441-[(S)-2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-pyrrolidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone 145(RS)-1-(2-Benzoruran-2-ylmethyl-piperidin-1-yl)-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 146(R)-1-[2-(4,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone and (S)-1-[2-(4,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoneand pharmaceutically acceptable salts thereof.

When a halogen atom is present in the compound of formula (I) it may befluorine, chlorine, bromine or iodine.

When the compound of formula (I) contains an alkyl group, whether aloneor forming part of a larger group, e.g. alkoxy or alkylthio, the alkylgroup may be straight chain, branched or cyclic, or combinationsthereof, it is preferably methyl or ethyl.

When used herein the term aryl means a 5- to 6-membered ring for examplephenyl, or a 7- to 12 membered bicyclic ring system where at least oneof the rings is aromatic for example naphthyl.

When used herein the term bicyclic hetero aryl means a 7- to 12 memberedbicyclic ring system where at least one of the rings is aromatic forexample benzimidazoyl, or tetrahydrobenzimidazolyl.

It will be appreciated that compounds of formula (I) may exist as R or Senantiomers. The present invention includes within its scope all suchisomers, including mixtures. Where additional chiral centres are presentin compounds of formula (I), the present invention includes within itsscope all possible diastereoismers, including mixtures thereof. Thedifferent isomeric forms may be separated or resolved one from the otherby conventional methods, or any given isomer may be obtained byconventional synthetic methods or by stereospecific or asymmetricsyntheses.

It will be understood that the invention includes pharmaceuticallyacceptable derivatives of compounds of formula (I) and that these areincluded within the scope of the invention.

Particular compounds according to the invention include those mentionedin the examples and their pharmaceutically acceptable derivatives.

As used herein “pharmaceutically acceptable derivative” includes anypharmaceutically acceptable salt, ester or salt of such ester of acompound of formula (I) which, upon administration to the recipient iscapable of providing (directly or indirectly) a compound of formula (I)or an active metabolite or residue thereof.

It will be appreciated that for use in medicine the salts of thecompounds of formula (I) should be pharmaceutically acceptable. Suitablepharmaceutically acceptable salts will be apparent to those skilled inthe art and include acid addition salts formed with inorganic acids e.g.hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; andorganic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric,benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.Other salts e.g. oxalates, may be used, for example in the isolation ofcompounds of formula (I) and are included within the scope of thisinvention. Also included within the scope of the invention are solvatesand hydrates of compounds of formula (I).

Certain of the compounds of formula (I) may form acid addition saltswith one or more equivalents of the acid. The present invention includeswithin its scope all possible stoichiometric and non-stoichiometricforms.

Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they areeach preferably provided in substantially pure form, for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions.

According to a further feature of the invention there is provided aprocess for the preparation of compounds of formula (I) and saltsthereof. The following schemes detail some synthetic routes to compoundsof the invention.

wherein, X, Het, and Ar² are as defined for compounds of formula (I), Pis a protecting group and M is a metal for example lithium.

Examples of suitable leaving groups L₁ include halogen, OC(═O)alkyl andOC(═O)O-alkyl. The transformation (II) to (I) may be carried out in aninert solvent such as dichloromethane, in the presence of a base such astriethylamine. Alternatively this step may be carried out when L¹represents hydroxy, in which case reaction with (II) takes place in aninert solvent such as dichloromethane in the presence of a diimidereagent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, and an activator such as 1-hydroxybenzotriazole.

Examples of protecting groups P include t-butyloxycarbonyl,trifluoroacetyl and benzyloxycarbonyl. Deprotection conditions arerespectively, acid (e.g. trifluoroacetic acid in dichloromethane), base(e.g. sodium hydroxide in a solvent such as aqueous methanol) andcatalytic hydrogenolysis in an inert solvent (e.g using palladium oncharcoal in a lower alcohol or ethyl acetate).

Compounds of formula (V) are known in the literature or can be preparedby known methods.

wherein, X, and Ar² are as defined for compounds of formula (I), Z is S,or O, and P is a protecting group.

wherein, X, and Ar² are as defined for compounds of formula (I) and P isa protecting group.

Examples of protecting groups P include t-butyloxycarbonyl,trifluoroacetyl and benzyloxycarbonyl. Deprotection conditions arerespectively, acid (e.g. trifluoroacetic acid in dichloromethane), base(e.g. sodium hydroxide in a solvent such as aqueous methanol) andcatalytic hydrogenolysis in an inert solvent (e.g using palladium oncharcoal in a lower alcohol or ethyl acetate).

The transformation of A to B can be carried out at elevated temperaturein the absence of solvent or in the presence of an acid such as sulfuricacid or polyphosphoric acid, usually at elevated temperature.Deprotection can occur in situ under acidic conditions, if for example Pis t-butoxycarbonyl to afford C directly.

Examples of suitable leaving groups L₁ include halogen, OC(═O)alkyl andOC(═O)O-alkyl. The transformation C to D may be carried out in an inertsolvent such as dichloromethane, in the presence of a base such astriethylamine. Alternatively this step may be carried out when L₁represents hydroxy, in which case reaction with C takes place in aninert solvent such as dichloromethane in the presence of a diimidereagent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, and an activator such as 1-hydroxybenzotriazole. Alsowhen L₁ represents hydroxy the reaction can be effected usingO-(7-azabenzotrazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) with a base such as triethylamine orN,N-diisopropylethylamine.

Wherein Het, X and Ar² are as defined for formula I and P is aprotecting group. Suitable reducing agents include sodium borohydridewhich can be used at ambient temperature in methanol.

Wherein Het, X and Ar² are as defined for formula I, P is a protectinggroup and M is a metal for example lithium.

Within the schemes above there is scope for functional groupinterconversion; conversion of one compound of formula (I) to another offormula (I) by interconversion of substituents.

The compounds of formula (I) may be prepared singly or as compoundlibraries comprising at least 2, e.g. 5 to 1000, preferably 10 to 100compounds of formula (I). Compound libraries may be prepared by acombinatorial ‘split and mix’ approach or by multiple parallel synthesisusing either solution phase or solid phase chemistry, by proceduresknown to those skilled in the art.

Thus according to a further aspect of the invention there is provided acompound library comprising at least 2 compounds of formula (I), orpharmaceutically acceptable derivatives thereof.

Pharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative.

The compounds of formula (I) and their pharmaceutically acceptablederivatives are useful for the treatment of diseases or disorders wherean antagonist of a human orexin receptor is required such as obesity anddiabetes; prolactinoma; hypoprolactinemia; hypothalamic disorders ofgrowth hormone deficiency; idiopathic growth hormone deficiency;Cushings syndrome/disease; hypothalamic-adrenal dysfunction; dwarfism;sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lagsyndrome; sleep disturbances associated with diseases such asneurological disorders, neuropathic pain and restless leg syndrome;heart and lung diseases; depression; anxiety; addictions; obsessivecompulsive disorder; affective neurosis/disorder; depressiveneurosis/disorder; anxiety neurosis; dysthymic disorder; behaviourdisorder; mood disorder; sexual dysfunction; psychosexual dysfunction;sex disorder; sexual disorder; schizophrenia; manic depression;delerium; dementia; bulimia and hypopituitarism. The compounds offormula (I) or pharmaceutically acceptable derivatives thereof are alsouseful in the treatment of stroke, particular ischaemic or haemorrhagicstroke. Furthermore the compounds of formula (I) or pharmaceuticallyacceptable derivatives useful in the blocking an emetic response.

The compounds of formula (I) and their pharmaceutically acceptablederivatives are particularly useful for the treatment of obesity,including obesity associated with Type 2 diabetes, and sleep disorders.Additionally the compounds are useful in stroke and/or blocking theemetic response i.e. nausea and vomiting.

A further aspect of the invention is the use of

-   R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine;-   (2R)-1-(3,5-dichlorobenzoyl)-2-[(1H-indol-3-yl)methyl]piperazine;-   (2R)-2-[1H-indol-3-yl)methyl]-1-[3-methoxy-5-trifluoromethyl)benzoyl]piperazine;    or-   1-benzolyl-2-[1H-indol-3-yl)methyl]piperazine;    as an orexin antagonist.

Other diseases or disorders which may be treated in accordance with theinvention include disturbed biological and circadian rhythms;adrenohypophysis disease; hypophysis disease; hypophysis tumor/adenoma;adrenohypophysis hypofunction; functional or psychogenic amenorrhea;adrenohypophysis hyperfunction; migraine; hyperalgesia; pain; enhancedor exaggerated sensitivity to pain such as hyperalgesia, causalgia andallodynia; acute pain; burn pain; atypical facial pain; neuropathicpain; back pain; complex regional pain syndromes I and II; arthriticpain; sports injury pain; pain related to infection e.g. HIV, post-poliosyndrome and post-herpetic neuralgia; phantom limb pain; labour pain;cancer pain; post-chemotherapy pain; post-stroke pain; post-operativepain; neuralgia; and tolerance to narcotics or withdrawal fromnarcotics.

The invention also provides a method of treating or preventing diseasesor disorders where an antagonist of a human orexin receptor is required,which comprises administering to a subject in need thereof an effectiveamount of a compound of formula (I), or a pharmaceutically acceptablederivative thereof.

The invention also provides a compound of formula (I), or apharmaceutically acceptable derivative thereof, for use in the treatmentor prophylaxis of diseases or disorders where an antagonist of a humanorexin receptor is required.

The invention also provides the use of a compound of formula (I), or apharmaceutically acceptable derivative thereof, in the manufacture of amedicament for the treatment or prophylaxis of diseases or disorderswhere an antagonist of a human orexin receptor is required.

A further aspect of the invention is the use of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazinein the manufacture of a medicament for the treatment or prophylaxis ofdiseases or disorders where an antagonist of a human orexin receptor isrequired.

For use in therapy the compounds of the invention are usuallyadministered as a pharmaceutical composition. The invention alsoprovides a pharmaceutical composition comprising a compound of formula(I), or a pharmaceutically acceptable derivative thereof, and apharmaceutically acceptable carrier.

The compounds of formula (I) and their pharmaceutically acceptablederivatives may be administered by any convenient method, e.g. by oral,parenteral, buccal, sublingual, nasal, rectal or transdermaladministration, and the pharmaceutical compositions adapted accordingly.

The compounds of formula (I) and their pharmaceutically acceptablederivatives which are active when given orally can be formulated asliquids or solids, e.g. as syrups, suspensions, emulsions, tablets,capsules or lozenges.

A liquid formulation will generally consist of a suspension or solutionof the active ingredient in a suitable liquid carrier(s) e.g. an aqueoussolvent such as water, ethanol or glycerine, or a non-aqueous solvent,such as polyethylene glycol or an oil. The formulation may also containa suspending agent, preservative, flavouring and/or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations, such as magnesium stearate, starch, lactose, sucrose andcellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures, e.g. pellets containing the active ingredientcan be prepared using standard carriers and then filled into a hardgelatin capsule; alternatively a dispersion or suspension can beprepared using any suitable pharmaceutical carrier(s), e.g. aqueousgums, celluloses, silicates or oils and the dispersion or suspensionthen filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe active ingredient in a sterile aqueous carrier or parenterallyacceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone,lecithin, arachis oil or sesame oil. Alternatively, the solution can belyophilised and then reconstituted with a suitable solvent just prior toadministration.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels and powders. Aerosol formulations typicallycomprise a solution or fine suspension of the active ingredient in apharmaceutically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container which can take the form of a cartridge or refill foruse with an atomising device. Alternatively the sealed container may bea disposable dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve. Where the dosage formcomprises an aerosol dispenser, it will contain a propellant which canbe a compressed gas e.g. air, or an organic propellant such as afluorochlorohydrocarbon or hydrofluorocarbon. Aerosol dosage forms canalso take the form of pump-atomisers.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles where the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

Compositions for rectal administration are conveniently in the form ofsuppositories containing a conventional suppository base such as cocoabutter.

Compositions suitable for transdermal administration include ointments,gels and patches.

Preferably the composition is in unit dose form such as a tablet,capsule or ampoule.

The dose of the compound of formula (I), or a pharmaceuticallyacceptable derivative thereof, used in the treatment or prophylaxis ofthe abovementioned disorders or diseases will vary in the usual way withthe particular disorder or disease being treated, the weight of thesubject and other similar factors. However, as a general rule, suitableunit doses may be 0.05 to 1000 mg, more suitably 0.05 to 500 mg. Unitdoses may be administered more than once a day for example two or threetimes a day, so that the total daily dosage is in the range of about0.01 to 100 mg/kg; and such therapy may extend for a number of weeks ormonths. In the case of pharmaceutically acceptable derivatives the abovefigures are calculated as the parent compound of formula (I).

No toxicological effects are indicated/expected when a compound offormula (I) is administered in the above mentioned dosage range.

Human orexin-A has the amino acid sequence:

pyroGlu Pro Leu Pro Asp Cys Cys Arg Gln Lys Thr Cys Ser Cys Arg Leu (SEQID NO: 1)  1              5                 10                  15 TyrGlu Leu Leu His Gly Ala Gly Asn His Ala Ala Gly Ile Leu Thr            20                 25                 30 Leu-NH₂

Orexin-A can be employed in screening procedures for compounds whichinhibit the ligand's activation of the orexin-1 receptor.

In general, such screening procedures involve providing appropriatecells which express the orexin-1 receptor on their surface. Such cellsinclude cells from mammals, yeast, Drosophila or E. coli. In particular,a polynucleotide encoding the orexin-1 receptor is used to transfectcells to express the receptor. The expressed receptor is then contactedwith a test compound and an orexin-1 receptor ligand to observeinhibition of a functional response. One such screening procedureinvolves the use of melanophores which are transfected to express theorexin-1 receptor, as described in WO 92/01810.

Another screening procedure involves introducing RNA encoding theorexin-1 receptor into Xenopus oocytes to transiently express thereceptor. The receptor oocytes are then contacted with a receptor ligandand a test compound, followed by detection of inhibition of a signal inthe case of screening for compounds which are thought to inhibitactivation of the receptor by the ligand.

Another method involves screening for compounds which inhibit activationof the receptor by determining inhibition of binding of a labelledorexin-1 receptor ligand to cells which have the receptor on theirsurface. This method involves transfecting a eukaryotic cell with DNAencoding the orexin-1 receptor such that the cell expresses the receptoron its surface and contacting the cell or cell membrane preparation witha compound in the presence of a labelled form of an orexin-1 receptorligand. The ligand may contain a radioactive label. The amount oflabelled ligand bound to the receptors is measured, e.g. by measuringradioactivity.

Yet another screening technique involves the use of FLIPR equipment forhigh throughput screening of test compounds that inhibit mobilisation ofintracellular calcium ions, or other ions, by affecting the interactionof an orexin-1 receptor ligand with the orexin-1 receptor.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following Examples illustrate the preparation of pharmacologicallyactive compounds of the invention. The Descriptions D1-D 83 illustratethe preparation of intermediates to compounds of the invention.

In the Examples ¹H NMR's were measured at 250 MHz in CDCl₃ unlessotherwise stated.

The following abbreviations are used herein;

PyBop means benzotriazol-1-yloxytris(pyrrolidino)phosphoniumhexafluorophosphate

THF means tetrahyrdofuran

EDC.HCL means 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride

HATU means O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

TFA means trifluoroacetatic acid

DMF means N,N-dimethylformamide

DME means 1,2-dimethoxyethane

DESCRIPTION 1(RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine

To (RS)-1-(tert-butyloxycarbonyl)-2-piperidine carboxylic acid (2.64 g,11.5 mmol) in dichloromethane (10 ml) was added sequentiallyN,O-dimethyl hydroxylamine (1.34 g, 13.7 mmol), triethylamine (6 ml,43.0 mmol) and Py.Bop (6.60 g, 12.7 mmol). The resultant mixture wasstirred at ambient temperature for 6 h, then diluted withdichloromethane (170 ml) and poured into 1M HCl (22 ml). The organicphase was separated and washed with saturated aqueous sodium hydrogencarbonate (3×25 ml) and brine (25 ml) then evaporated in vacuo. Theresultant colourless oil was chromatographed on silica gel eluting with20% ethyl acetate in hexane to give the title compound (2.43 g, 77%) asa colourless oil.

Mass spectrum (API⁺): Found 273 (MH⁺). C₁₃H₂₄N₂O₄ requires 272.

DESCRIPTION 2(RS)-2-(2-Benzofuranylcarbonyl)-1-(tert-butyloxycarbonyl)piperidine

To a solution of benzofuran (0.37 ml, 3.36 mmol) in THF (40 ml) at −35°C. was added nbutyllithium (1M in THF) (3.34 ml, 3.34 mmol) over 3 min.The resultant mixture was stirred for 10 min. at −35° C. then(RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine(1.0 g, 3.68 mmol) in THF (5 ml) was added over 1 min. and the resultantsolution stirred for 15 min. at −35° C. The mixture was poured intosaturated ammonium chloride (20 ml) and extracted with ethyl acetate(3×20 ml). The combined organics were washed with saturated aqueoussodium hydrogen carbonate (15 ml), then evaporated in vacuo. Theresultant residue was chromatographed on silica gel eluting with 10%ethyl acetate in hexane to give the title compound (0.32 g, 26%) as ayellow solid.

Mass spectrum (API⁺): Found 330 (MH⁺) C₁₉H₂₃NO₄ requires 329.

DESCRIPTION 3 (RS)-2-(2-Benzofuranylmethyl)piperidine

To a solution of(RS)-2-(2-benzofuranylcarbonyl)-1-(tert-butyloxycarbonyl)piperidine(0.30 g, 0.91 mmol) in diethylene glycol (20 g), was added hydrazinehydrate (0.16 ml, 2.79 mmol) and the resultant mixture heated at 170° C.for 30 min. then cooled to room temperature. Potassium hydroxide (0.44g, 7.86 mmol) was added and the mixture heated at 200° C. for 18 h. Theresultant was then poured into water (100 ml) and extracted with diethylether (3×20 ml). The combined organic extracts were dried (Na₂SO₄) andevaporated in vacuo to give the title compound (10 mg, 36%) as a goldenoil.

Mass spectrum (API⁺). Found 216 (MH⁺) C₁₄H₁₇NO requires 215.

DESCRIPTION 4(RS)-2-[(2-Hydroxy-phenylcarbamoyl)-methyl]-piperidine-1-carboxylic acidtert butyl ester

A mixture of 2-carboxymethyl-piperidine-1-carboxylic acid tert butylester (0.97 g), (Peschke, Bernd; Ankersen, Michael; Hansen, BirgitSehested; Hansen, Thomas Kruse; Johansen, Nils Langeland; Lau, Jesper;Madsen, Kjeld; Petersen, Hans; Thogersen, Henning; Watson, Brett. Eur.J. Med. Chem. (1999), 34(5), 363-380) in dimethylformamide (8.0 ml) wastreated sequentially with EDC.HCl (0.76 g), 2-aminophenol (0.43 g) and1-hydroxybenzotriazole (0.05 g). The mixture was stirred for 2 h,diluted with ethyl acetate and washed with water, dried (MgSO₄) andsolvent removed at reduced pressure to give the title compound (1.29 g)as a gum.

Mass Spectrum (API⁺): Found 335 (MH⁺). C₁₈H₂₆N₂O₄ requires 334

DESCRIPTION 5 (RS)-2-Benzooxazol-2-ylmethyl-piperidine-1-carboxylic acidtert butyl ester

(RS)-2-[(2-Hydroxy-phenylcarbamoyl)-methyl]-piperidine-1-carboxylic acidtert butyl ester (1.25 g), 4-toluenesulphonic acid (0.07 g) and4-N,N-dimethylaminopyridine (0.023 g) were combined in1,3-dichlorobenzene (30 ml) and the mixture boiled for 48 h. The mixturewas diluted with dichloromethane and washed with water. The organicphase was dried (MgSO₄) and solvent removed at reduced pressure. Theresidue was column chromatographed (silica gel, 0→1% methanol indichloromethane) to give the title compound (0.50 g)

Mass Spectrum (API⁺): Found 317 (MH⁺). C₁₈H₂₄N₂O₃ requires 316.

DESCRIPTION 6 (RS)-2-Piperidin-2-ylmethyl-benzooxazole

(RS)-2-Benzooxazol-2-ylmethyl-piperidine-1-carboxylic acid tert butylester (0.50 g) in dichloromethane (8 ml) was cooled (ice-bath) andtrifluoroacetic acid (2 ml) added. The mixture was stirred withice-cooling for 4 h, poured onto saturated potassium carbonate (20 ml)and extracted with dichloromethane. The combined extracts were dried(MgSO₄) and solvent removed at reduced pressure to give the titlecompound (0.10 g)

Mass Spectrum (API⁺): Found 217 (MH⁺). C₁₃H₁₆N₂O requires 216.

DESCRIPTION 7(RS)-2-[1-(5-Fluoro-benzofuran-2-yl)methanoyl)-piperidine-1-carboxylicacid tert-butyl ester

The title compound was prepared using the method of Description 2, from5-fluorobenzofuran (1.36 g, 10 mmol, for preparation see WO99/51575), asa pale yellow solid (2.81 g, 84%)

¹H NMR δ: 1.20-1.60 (1H, m), 1.60-1.85 (2H, m), 1.90 (1H, broad m),2.15-2.30 (1H, broad m), 3.20-3.40 (1H, broad m), 3.85-4.05 (1H, broadm), 5.20-5.70 (1H, broad m), 7.10-7.25 (1H, m), 7.25-7.4 (1H, d, J=7.4Hz), 7.45-7.75 (2H, m).

DESCRIPTION 8 (RS)-2-(5-Fluoro-benzofuran-2-ylmethyl)-piperidine

The title compound was prepared using the method of Description 3, from(RS)-2-[1-(5-Fluoro-benzofuran-2-yl)methanoyl)-piperidine-1-carboxylicacid tert-butyl ester, D7 (1.21 g, 3.49 mmol), as a pale yellow gum(0.72 g, 89%).

Mass spectrum (API⁺): Found 234 (MH⁺) C₁₄H₁₆FNO requires 233.

DESCRIPTION 9 (RS)-1-Benzofuran-2-yl-1-piperidin-2-yl-methanone

A solution of(RS)-2-(2-benzofuranylcarbonyl)-1-(tert-butyloxycarbonyl)piperidine, D2(0.86 g, 2.61 mmol) in trifluoroacetic acid (5 ml) and dichloromethane(20 ml) was warmed at 35° C. for 0.5 h. The reaction mixture wasevaporated in vacuo and the residue partitioned between dichloromethane(30 ml) and 1N sodium hydroxide (30 ml). The aqueous layer was extractedwith dichloromethane (30 ml) and the combined organic layers dried(Na₂SO₄) and evaporated in vacuo to afford the title compound as a paleyellow gum (0.59 g, 99%).

Mass spectrum (API⁺): Found 230 (MH⁺). C₁₄H₁₅NO₂ requires 229.

DESCRIPTION 10(RS)-2-(1-Furo[2,3-b]pyridin-2-yl)methanoyl-piperidine-1-carboxylic acidtert-butyl ester

2.5N n-Butylithium in hexanes (2.3 ml, 5.75 mmol) was added dropwiseover 10 min to a stirred solution of furo[2,3-b]pyridine (0.57 g, 4.79mmol) (H. Sliwa, Bull. Soc. Chim. France, 646, 1970) in anhydrous THF(20 ml) at −75° C. under argon. The resultant mixture was stirred for 5min at −70° C. then a solution of(RS)-1-(tert-butyloxycarbonyl)-2-1-methoxy-N-methylcarbamoyl)-piperidine,D1 (1.41 g, 5.19 mmol) in anhydrous THF (20 ml) was added over 2 min.and the resultant solution stirred at −70° C. for 15 min. The mixturewas poured into saturated ammonium chloride (100 ml) and extracted withethyl acetate (2×50 ml). The combined organics were dried (Na₂SO₄) andevaporated in vacuo. The residue was chromatographed on silica geleluting with 0-1% ethyl acetate in dichloromethane to give the titlecompound as a colourless solid (0.51 g, 32%).

¹H NMR δ: 1.25-1.55 (11H, m), 1.60-1.80 (2H, m), 1.85-2.05 (1H, broadm), 2.15-2.40 (1H, broad m), 3.15-3.40 (1H, broad m), 3.80-4.15 (1H,broad m), 5.35-5.65 (1H, broad m), 7.30 (1H, broad m), 7.56 (1H, broads), 8.08 (1H, broad m), 8.53 (1H, broad m).

DESCRIPTION 11 (RS)-2-Piperidin-2-ylmethyl-furo[2,3-b]pyridine

The title compound was prepared using the method of Description 3, from(RS)-2-(1-furo[2,3-b]pyridin-2-yl)methanoyl)piperidine-1-carboxylic acidtert-butyl ester, D10 (0.51 g, 1.55 mmol), as a light brown gum (0.26 g,74%).

Mass spectrum (API⁺): Found 217 (MH⁺) C₁₃H₁₆N₂O requires 216.

DESCRIPTION 12(RS)-2-(1-Quinolin-2-yl-methanoyl)-piperidine-1-carboxylic acidtert-butyl ester

30% Potassium hydride dispersed in mineral oil (0.8 g, 6 mmol) was addedto a stirred solution of 2-bromoquinoline (1.12 g, 5.29 mmol) (O.Sugimoto, Tet. Lett. 4, (1999), 7477-8) in anhydrous THF (20 ml) at −70°C. under argon. To this was added 2N n-butyllithium in hexanes (2.7 ml,6.75 mmol) dropwise over 5 min. The resultant mixture was stirred for 10min at −70° C. then a solution of(RS)-1-(tert-butyloxycarbonyl)-2-1-methoxy-N-methylcarbamoyl)-piperidine,D1 (1.57 g, 5.77 mmol) in anhydrous THF (10 ml) was added over 2 min.The cooling bath was removed and the reaction mixture allowed to warm to−20° C. and held at −20° C. for 10 min. The mixture was poured intosaturated ammonium chloride (300 ml) and extracted with ethyl acetate(2×100 ml). The combined organics were dried (Na₂SO₄) and evaporated invacuo. The residue was chromatographed on silica gel eluting with 0-10%ethyl acetate in pentane to yield the title compound as a pale yellowsolid (1.2 g, 66%).

¹H NMR δ: 1.2-1.65 (12H, m), 1.65-1.85 (1H, m), 1.90-2.10 (1H, m),2.20-2.50 (1H, m), 3.30-3.60 (1H, m), 3.85-4.20 (1H, m), 6.20-6.40 (1H,m), 7.50-7.90 (3H, m), 8.07 (1H, d, J=8.4 Hz), 8.18 (1H, d, J=8.8 Hz),8.20-8.35 (1H, m).

DESCRIPTION 13 (RS)-2-Piperidin-2-ylmethyl-quinoline

The title compound was prepared using the method of Description 3, from(RS)-2-(1-quinolin-2-yl-methanoyl)-piperidine-1-carboxylic acidtert-butyl ester, D12 (1.2 g, 3.66 mmol), as a pale brown gum (0.053 g,6%)

Mass spectrum (Electrospray LC/MS): Found 227 (MH⁺). C₁₅H₁₈N₂ requires226.

DESCRIPTION 14 2-Amino-N,N-dimethyl-3-nitro-benzamide

EDC.HCl (2.47 g, 12.88 mmol) was added to a stirred mixture of2-amino-3-nitrobenzoic acid (2.18 g, 11.98 mmol) (Mickelson, J. Med.Chem, 39(23) 4662 (1996)), 2M dimethylamine in THF (6.45 ml, 12.9 mmol)and 1-hydroxybenzotriazole (0.1 g, 0.74 mmol) in dichloromethane (100ml). The reaction mixture was stirred at room temperature for 18 h,washed with saturated aqueous sodium bicarbonate and the organic layerdried (Na₂SO₄) and evaporated in vacuo to afford the title compound as apale orange gum (2.5 g, 100%).

¹H NMR δ: 3.08 (6H, s), 6.70 (1H, m), 6.85 (2H, broad s), 7.33 (1H, dd,J=2 and 8 Hz), 8.2 (1H, dd, J=2 and 8 Hz).

DESCRIPTION 15 3-Dimethylaminomethyl-benzene-1,2-diamine

1M Lithium aluminium hydride in THF (18.1 ml, 18.1 mmol) was addeddropwise over 5 min. to a stirred, ice cooled solution of2-Amino-N,N-dimethyl-3-nitro-benzamide, D14 (1.26 g, 6.03 mmol) inanhydrous THF (40 ml) under argon. The reaction mixture was stirred at0° C. for 0.5 h then at room temperature for a further 2 h before beingrecooled in ice, as water (3.2 ml), 2N sodium hydroxide (3.6 ml) andwater (3.2 ml) were added dropwise sequentially. The mixture was stirredfor 10 min, solid Na₂SO₄ added and stirring continued for 10 min. Solidswere filtered, washed with ethyl acetate and the combined organicsevaporated in vacuo to give the title compound as an orange solid (0.9g, 91%).

¹H NMR δ: 2.19 (6H, s), 3.29 (2H, broad s), 3.42 (2H, s), 4.50 (2H,broad s), 6.50-6.80 (3H, m).

DESCRIPTION 16(RS)-(1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-yl)-aceticacid methyl ester

A stirring solution of5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (3.00 g, 12.5mmol) in DMF (50 ml), under argon was treated sequentially withN,N-diisopropylethylamine (6.8 ml), HATU (4.77 g, 12.5 mmol) then afterstirring for 0.25 h, piperidin-2-yl-acetic acid methyl ester (Beckett etal, J. Med. Chem., 563, 1969) (1.83 g, 12.5 mmol) was added. The mixturewas stirred for 16 h at room temperature and was then diluted withwater. The product was extracted into diethyl ether. The organic phasewas washed with water (3×) and brine, was dried (MgSO₄) and the solventremoved in vacuo to afford the title compound as a yellow gum (4.00 g,85%).

Mass spectrum (API⁺). Found 377 (MH⁺). C₁₉H₂₁FN₂O₃S requires 376.

DESCRIPTION 17(RS)-(1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-yl)-aceticacid

A stirring solution of(1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-yl)-aceticacid methyl ester, D16 (4.00 g, 10.6 mmol) in methanol/water (75 ml/25ml) was treated with sodium hydroxide (0.85 g, 21.3 mmol). The mixturewas stirred for 16 h at room temperature. The methanol was removed invacuo and the residue was diluted with water and extracted with diethylether (2×). The aqueous phase was acidified with 5N HCl and the productwas extracted with ethyl acetate. The organic phase was dried (MgSO₄)and the solvent removed in vacuo. The residue was triturated withpentane to afford the title compound as a white solid (3.10 g, 82%).

¹H NMR (D₆-DMSO) δ: 0.98 (0.6H, m), 1.15-1.70 (5.4H, bm), 2.18 (0.4H,dd), 2.38 (0.6H, dd, J=6 and 15 Hz), 2.70 (4.4H, m), 2.93 (0.6H, m),3.17 (0.6H, d, J=12 Hz), 3.94 (0.4H, m), 4.40 (0.4H, d, J=12 Hz), 5.05(0.6H, m), 7.27 (2H, m), 7.47 (2H, m), 12.20 (1H, bs).

DESCRIPTION 18(RS)-5,6-Difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole

A mixture of 2-carboxymethyl-piperidine-1-carboxylic acid tert-butylester (Beckett et al, J. Med. Chem., 563, 1969) (10.0 g, 41 mmol) and4,5-difluoro-benzene-1,2-diamine (5.95 g, 41 mmol) in polyphosphoricacid (140 g) was heated at 140° C. for 7 h. The cooled reaction mixturewas poured onto excess solid potassium carbonate and crushed ice. Theresulting basic, aqueous solution was extracted with ethyl acetate (2×)and the combined organics were washed with brine, dried (Na₂SO₄) and thesolvent removed in vacuo. The residue was triturated with diethyl ether,ethyl acetate and pentane to afford the title compound as a light brownsolid (7.14 g, 69%).

¹H NMR (D₆-DMSO) δ: 1.08 (1H, m), 1.27 (2H, m), 1.50 (2H, m), 1.70 (1H,m), 2.48 (1H, m, obscured by DMSO), 2.78 (2H, d, J=7 Hz), 2.88 (2H, m),7.51 (2H, app. t, J=6 Hz).

DESCRIPTION 19(RS)-2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidine-1-carboxylicacid tert-butyl ester

4,5-Difluoro-benzene-1,2-diamine (1.00 g, 6.9 mmol) and2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (Beckettet al, J. Med. Chem., 563, 1969) (1.69 g, 6.9 mmol) were heated at 120°C. with stirring, under argon for 4 h. A further portion of2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.85 g)was added and heating was continued for a further 2 h. The cooledreaction mixture was diluted with ethyl acetate, washed with saturatedaqueous sodium bicarbonate (2×) and brine, dried (MgSO₄) and the solventremoved in vacuo. The residue was chromatographed (silica gel, 0-30%ethyl acetate-pentane) to give a yellow solid which was triturated withdiethyl ether to afford the title compound as a pale brown solid (0.38g, 15%).

Mass spectrum (API⁺). Found 352 (MH⁺) C₁₈H₂₃F₂N₃O₂ requires 351.

DESCRIPTION 20(RS)-5,6-Difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole. 2HCl

A stirring solution of2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidine-1-carboxylicacid tert-butyl ester, D19 (375 mg, 1.1 mmol) in MeOH (20 ml) wastreated with 1M HCl in 1,4-dioxane (5 ml). After stirring under argon atroom temperature for 5 h the volatiles were removed in vacuo to affordthe title compound as a gum (100%).

Mass spectrum (API⁺). Found 252 (MH⁺) C₁₃H₁₅F₂N₃ requires 251.

DESCRIPTION 21(RS)-4,5-Difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole

A mixture of 2-carboxymethyl-piperidine-1-carboxylic acid tert-butylester (Beckett et al, J. Med. Chem., 563, 1969) (6.72 g, 28 mmol) and3,4-difluoro-benzene-1,2-diamine (4.00 g, 28 mmol) in polyphosphoricacid (130 g) was heated at 140° C. for 7.5 h. The cooled reactionmixture was poured onto excess solid potassium carbonate and crushedice. The resulting basic, aqueous solution was extracted with ethylacetate (2×) and the combined organics were washed with brine, dried(Na₂SO₄) and the solvent removed in vacuo. The residue was trituratedwith diethyl ether, ethyl acetate and pentane to afford the titlecompound as a white solid (4.29 g, 62%).

¹H NMR (D₆-DMSO) δ: 1.08 (1H, m), 1.28 (2H, m), 1.50 (2H, m), 1.72 (1H,m), 2.46 (1H, m, obscured by DMSO), 2.81 (2H, d, J=7 Hz), 2.90 (2H, m),7.14 (1H, m), 7.24 (1H, m).

DESCRIPTION 221-(2-Dimethylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrazole-3-carboxylicacid ethyl ester

4-(4-Fluoro-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (2.4 g, 10mmol) was added to an ice-cooled slurry of sodium hydride (0.82 g, 60%dispersion in mineral oil, 20 mmol) in DMF (20 ml), under argon.N,N-diisopropylethylamine (1.8 ml, 10 mmol) was added followed by2-chloro-ethyl dimethylamine.HCl (1.48 g, 10 mmol) and potassium iodide(5 mg). The reaction mixture was stirred at room temperature for 16 hthen at 80° C. for 48 h. 2N HCl and water were added and the productextracted with ethyl acetate (3×). The combined organics were washedwith brine, dried (Na₂SO₄) and the solvent removed in vacuo.Chromatography (silica gel, 3-10% methanol-dichloromethane) afforded2-(2-dimethylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrazole-3-carboxylicacid ethyl ester (900 mg) and the title compound (630 mg).

¹H NMR δ: 1.31 (3H, t. J=7 Hz), 2.29 (6H, s), 2.80 (2H, t, J=6 Hz), 4.30(4H, m), 7.05 (2H, m), 7.44 (2H, m), 7.56 (1H, s).

DESCRIPTION 231-(2-Dimethylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrazole-3-carboxylicacid

A solution of1-(2-Dimethylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrazole-3-carboxylicacid ethyl ester, D22 (610 mg, 2 mmol) in methanol/water (15 ml/10 ml)was treated with 2N sodium hydroxide (4 ml). After stirring at roomtemperature for 16 h the methanol was removed in vacuo and the residuetreated with 2N HCl (4 ml). The water was removed in vacuo.Dichloromethane was added to the residue and the inorganic solid wasremoved by filtration. Removal of the solvent form the filtrate in vacuoafforded the title compound as a white solid (350 mg, 63%).

Mass spectrum (API⁺). Found 278 (MH⁺) C₁₄H₁₆FN₃O₂ requires 277.

DESCRIPTION 245-(4-Fluoro-phenyl)-2-methyl-2H-[1,2,3]triazole-4-carboxylic acid methylester

5-(4-Fluoro-phenyl)-2H-[1,2,3]triazole-4-carboxylic acid methyl ester(2.21 g, 10 mmol) in THF (10 ml) was added drop-wise to an ice-cooledslurry of sodium hydride (0.42 g, 60% dispersion in mineral oil, 10mmol) in THF (45 ml), under argon. After stirring at room temperaturefor 1 h, the reaction mixture was heated at 80° C. for 16 h. Water wasadded to the cooled mixture and the product was extracted with diethylether (2×). The combined organics were washed with brine, dried (Na₂SO₄)and the solvent removed in vacuo. Chromatography (silica gel, 10-50%ethyl acetate-pentane) afforded5-(4-Fluoro-phenyl)-1-methyl-2H-[1,2,3]triazole-4-carboxylic acid methylester (763 mg, 33%) and the title compound (943 mg, 40%).

¹H NMR δ: 3.94 (3H, s), 4.29 (3H, s), 7.13 (2H, m), 7.87 (2H, m).

DESCRIPTION 255-(4-Fluoro-phenyl)-2-methyl-2H-[1,2,3]triazole-4-carboxylic acid

5-(4-Fluoro-phenyl)-2-methyl-2H-[1,2,3]triazole-4-carboxylic acid methylester D24 (940 mg, 4 mmol) in water (65 ml) was treated with 2N sodiumhydroxide (4 ml) and the mixture was heated at 120° C. for 2 h. Thevolume of water was reduced to 20 ml in vacuo and the ice-cooled residuewas treated with 2N HCl (4 ml). Filtration, washing with water anddrying in vacuo afforded the title compound as a white solid (810 mg,91%).

Mass spectrum (API⁺). Found 222 (MH⁺) C₁₀H₈FN₃O₂ requires 221.

DESCRIPTION 26 (S)-Pyrrolidin-2-ylmethyl-1H-benzoimidazole

A mixture of benzene-1,2-diamine (0.235 g, 2.2 mmol) and(S)-2-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester(0.500 g, 2.2 mmol) in polyphosphoric acid (10 g) was heated under argonat 140° C. for 4 h then at 160° C. for 20 h. The reaction mixture wascooled and partitioned between aqueous saturated potassium carbonate anddichloromethane. The aqueous phase was extracted with 9-1dichloromethane-methanol (4×). The combined organics were dried (MgSO₄)and the solvent removed in vacuo to afford the title compound as a palebrown foam (0.328 g) contaminated with 9% starting diamine.

¹H NMR δ: 1.30-2.10 (4H, bm), 2.80-3.60 (6H, bm incl. NH), 7.20 (1H, m),7.55 (1H, m).

DESCRIPTION 27 (S)-5,6-Difluoro-pyrrolidin-2-ylmethyl-1H-benzoimidazole

A mixture of 4,5-difluorobenzene-1,2-diamine (0.360 g, 2.5 mmol) and(S)-2-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester(0.570 g, 2.5 mmol) in polyphosphoric acid (9.5 g) was heated underargon at 160° C. for 20 h. The reaction mixture was cooled andpartitioned between aqueous saturated potassium carbonate anddichloromethane. The aqueous phase was extracted with 9-1dichloromethane-methanol (4×). The combined organics were dried (MgSO₄)and the solvent removed at reduced pressure to afford the title compoundas a pale brown foam (0.394 g).

Mass Spectrum (API⁺): Found 236 (M-H). C₁₂H₁₃F₂N₃ requires 237.

DESCRIPTION 28 (RS)-[1-(2,2,2-Trifluoroethanoyl)-piperidin-2-yl]aceticacid ethyl ester

(RS)-Piperidin-2-yl acetic acid ethyl ester (Rhodes et al, J. Am. Pharm.Assoc., 1956, 45, 746) (6.0 g) was dissolved in dry dichloromethane (60ml) and cooled to −10° C. under an atmosphere of argon. Triethylamine(5.0 ml), followed by trifluoroacetic anhydride (5.1 ml) was added tothe stirred solution and stirring was continued at room temperature for16 h. The reaction solution was then partitioned between dichloromethaneand saturated sodium bicarbonate solution. The organic solution wasdried (MgSO₄) and the solvent removed in vacuo to yield the titlecompound as an oil (4.2 g).

Mass Spectrum (API⁺): Found 268 (MH⁺). C₁₁H₁₆F₃NO₃ requires 267.

DESCRIPTION 29(R,S)-1-(2-Benzothiazol-2-ylmethylpiperidin-1-yl)-2,2,2-trifluoro-ethanone

[1-(2,2,2-Trifluoroethanoyl)piperidin-2-yl]acetic acid ethyl ester, D28(1.34 g) and 2-aminothiophenol (1.50 g) were suspended in polyphosphoricacid (30 ml) and heated to 90° C. for 2 h with vigorous stirring. Aftercooling, the reaction mixture was poured into iced water and stirredvigorously for 1 h. The aqueous solution was then extracted severaltimes with ethyl acetate. After drying (MgSO₄), the solvent was removedin vacuo and the residue chromatographed (silica gel) to afford thetitle compound as an oil (1.2 g).

Mass Spectrum (API⁺): Found 329 (MH⁺). C₁₅H₁₅F₃N₂SO requires 328.

DESCRIPTION 30 (RS)-2-Piperidin-2-ylmethylbenzothiazole

1-(2-Benzothiazol-2-ylmethylpiperidin-1-yl)-2,2,2-trifluoroethanone, D29(1.2 g) was dissolved in methanol (40 ml) and 2N sodium hydroxidesolution (20 ml) and heated to 50° C. for 0.75 h. After cooling, thereaction solution was partitioned between dichloromethane and water. Theorganic solution was dried (MgSO₄) and the solvent removed in vacuo. Theresidue was chromatographed (silica gel, 0-10% [9:1 MeOH/conc. ammoniasolution] in dichloromethane) to afford the title compound (0.68 g).

Mass Spectrum (API⁺): Found 233 (MH⁺). C₁₃H₁₆N₂S requires 232.

DESCRIPTION 31 (RS)-1-Benzyl-2-bromomethylpiperidine

(RS)-(1-Benzyl-piperidin-2-yl)-methanol (R. Sreekumar et al, TetrahedronLett., 1998, 39 5151) (10.0 g) was converted to the title compound (5.2g) by treatment with triphenylphosphine (13.0 g) and N-bromosuccinimide(9.4 g) in dichloromethane using literature procedures, (TetrahedronLett, 1999, 40, 7477-8).

Mass Spectrum (API⁺): Found 270 (MH⁺). C₁₃H₁₈ ⁸¹BrN requires 269.

DESCRIPTION 32 (RS)-1-Benzyl-2-cyanomethylpiperidine

(RS)-1-Benzyl-2-bromomethylpiperidine, D31 (4.2 g) was dissolved in drydimethylsulphoxide (15 ml) and treated with sodium cyanide (5.0 g). Thesolution was then stirred at 85° C. under argon for 18 h. The reactionsolution was then poured into water (300 ml) and extracted withdichloromethane (2×200 ml). The organic solution was dried (MgSO₄) andthe solvent removed in vacuo. Chromatography (silica gel, diethylether/petroleum ether mixtures) afforded the title compound (3.3 g).

Mass Spectrum (API⁺): Found 215 (MH⁺). C₁₄H₁₈N₂ requires 214.

DESCRIPTION 33(RS)-2-(1-Benzylpiperidin-2-ylmethyl)-[1,2,4]-triazolo[1,5-a]pyridine

(RS)-1-Benzyl-2-cyanomethylpiperidine, D32 (1.0 g) was dissolved in drytetrahydrofuran (10 ml) containing ethanol (0.28 ml). The reactionsolution was then cooled to ice bath temperature and hydrogen chloridegas was bubbled through the solution for 1 h. The solution was thenstirred at room temperature for 16 h. The resulting solution was dilutedwith tetrahydrofuran (30 ml) and dichloromethane (30 ml) and1-aminopyridinium iodide (1.0 g), followed by excess potassium carbonateand ethanol (30 ml) was added. The reaction mixture was then stirred atroom temperature under argon for 24 h. The mixture was then filtered andthe solvent removed in vacuo. The residue was chromatographed (silicagel, 80-20 diethyl ether-petroleum ether then 9-1dichloromethane-methanol) to afford the title compound.

Mass Spectrum (API⁺): Found 307 (MH⁺). C₁₄H₁₈N₂ requires 306.

DESCRIPTION 34(RS)-2-Piperidin-2-ylmethyl-5,6,7,8-tetrahydro-[1,2,4]-triazolo[1,5-a]pyridineand 2-Piperidin-2-ylmethyl-[1,2,4]-triazolo[1,5-a]pyridine

(RS)-2-(1-Benzylpiperidin-2-ylmethyl)-[1,2,4]-triazolo[1,5-a]pyridine,D33 (0.200 g) was dissolved in ethanol (25 ml). Palladium hydroxide(0.100 g), followed by platinum IV sulphide (0.020 g) were added and thereaction mixture hydrogenated at 50 psi and 50° C. for 16 h. Thesuspension was evaporated to yield a mixture of the title compounds(0.180 g).

DESCRIPTION 35(RS)-2-[(Methoxy-methyl-carbamoyl)-methyl]-piperidine-1-carboxylic acidtert-butyl ester

A solution of 2-carboxymethyl-piperidine-1-carboxylic acid tert-butylester (Beckett et al, J. Med. Chem., 563, 1969) (2.29 g, 10 mmol) in DMF(20 ml) was treated sequentially with N,N-diisopropylethylamine (4.0ml), HATU (3.8 g, 10 mmol) and O,N-dimethyl-hydroxylamine.HCl (0.98 g,10 mmol). The reaction mixture was stirred under argon at roomtemperature for 16 h. The volatiles were removed in vacuo and theresidue was chromatographed (silica gel, diethyl ether) to afford thetitle compound as a white solid (2.60 g, 90%).

Mass Spectrum (API⁺): Found 187 (MH⁺—^(t)BOC). C₁₄H₂₆N₂O₄ requires 286.

DESCRIPTION 36(RS)-2(2-Benzofuran-2-yl-2-oxo-ethyl)-piperidine-1-carboxylic acidtert-butyl ester

To a solution of benzofuran (0.95 g, 8.0 mmol) in THF (40 ml), underargon at −40° C. was added n-butyllithium (2.5M in hexanes) (4.00 ml,10.0 mmol) over 5 min. The resultant mixture was stirred for 15 min. at−40° C. then(RS)-2-[(methoxy-methyl-carbamoyl)-methyl]-piperidine-1-carboxylic acidtert-butyl ester, D35 (2.30 g, 8.0 mmol) in THF (10 ml) was added over 1min. and the resultant solution stirred for 20 min. at −40° C. Themixture was poured into saturated ammonium chloride (20 ml) andextracted with ethyl acetate (3×). The combined organics were dried(MgSO₄) and the solvent removed in vacuo. The resultant residue waschromatographed (silica gel, dichloromethane) to afford the titlecompound (2.2 g, 84%).

¹H NMR δ: 1.35 (9H, s), 1.44 (1H, m), 1.65 (5H, m), 2.94 (1H, dt, J=3and 13 Hz), 3.17 (2H, m), 4.05 (1H, broad d), 4.89 (1H, m), 7.31 (1H, t,J=8 Hz), 7.48 (1H, m), 7.57 (2H, m), 7.72 (1H, d, J=8 Hz).

DESCRIPTION 37 (RS)-1-Benzofuran-2-yl-2-piperidin-2-yl-ethanone

A stirring solution of(RS)-2(2-benzofuran-2-yl-2-oxo-ethyl)-piperidine-1-carboxylic acidtert-butyl ester, D36 (1.68 g, 4.9 mmol) in dichloromethane (20 ml) wastreated with trifluoroacetic acid (5 ml). The mixture was stirred at 50°C. for 1 h, cooled and the volatiles removed in vacuo.

The residue was dissolved in dichloromethane and washed with saturatedsodium bicarbonate, dried (MgSO₄) and the solvent removed in vacuo toafford the title compound (1.20 g, 99%).

Mass Spectrum (API⁺): Found 244 (MH⁺). C₁₅H₁₇NO₂ requires 243.

DESCRIPTION 38(RS)-1-Benzofuran-2-yl-2-(1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-yl)-ethanone

The title compound was prepared from5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid

and (RS)-1-benzofuran-2-yl-2-piperidin-2-yl-ethanone, D37 according to aprocedure similar to that for Description 35.

Mass Spectrum (API⁺): Found 463 (MH⁺). C₂₆H₂₃FN₂O₃S requires 462.

DESCRIPTION 39 (RS)-4-Bromo-2-piperidin-2-ylmethyl-1H-benzimidazole

The title compound was prepared using the method of Description 18 from3-bromobenzene-1,2-diamine (0.50 g, 2.7 mmol) and2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.65 g,2.7 mmol), as a pale brown amorphous solid (0.70 g, 88%)

Mass spectrum (Electrospray LC/MS): Found M-H 292. C₁₃H₁₆ ⁷⁹BrN₃requires 293.

DESCRIPTION 40(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-2,2,2-trifluoro-ethanone

To (RS)-2-(2-Benzofuranylmethyl)piperidine, D3 (500 mg, 2.3 mmol) indichloromethane containing triethylamine (0.35 ml, 2.5 mmol) at 0° C.under argon was added trifluoroacetic anhydride (0.36 ml, 2.5 mmol) indichloromethane (3 ml) over 5-10 min. The reaction was stirred at roomtemperature for 64 h, diluted with dichloromethane and washedsequentially with water and saturated sodium hydrogen carbonate, dried(Na₂SO₄) and the solvent removed in vacuo. Chromatography (silica gel)afforded the title compound as a solid (740 mg, 99%).

¹H NMR δ: 1.50-1.90 (6H, m), 2.90-3.20 (2H, m), 3.27-3.35 (1H, m),3.85-3.89 (0.66H, m), 4.51-4.54 (0.66H, m), 5.09-5.14 (0.66H, m), 6.48and 6.50 (1H, s), 7.15-7.25 (2H, m), 7.39-7.45 (1H, m), 7.45-7.50 (1H,m).

DESCRIPTION 41(RS)-1-(2-(3-Bromo-benzofuran-2-ylmethyl-piperidin-1-yl)-2,2,2-trifluoro-ethanone

To a solution of(RS)-1-(2-benzofuran-2-ylmethyl-piperidin-1-yl)-2,2,2-trifluoro-ethanone,D40 (700 mg, 2.2 mmol) in diethyl ether (10 ml) at −12° C. under argonwas added a solution of bromine (360 mg, 2.2 mmol) in dichloromethane (4ml) drop-wise over 0.3 h. The reaction mixture was allowed to reach roomtemperature and after 1 h the volatiles were removed in vacuo.Re-evaporation from dichloromethane (3×) afforded the title compound asa solid (840 mg, 96%).

Mass spectrum (Electrospray LC/MS): Found 310 (MH⁺—Br). C₁₆H₁₅ ⁷⁹BrF₃NO₂requires 389.

DESCRIPTION 42(RS)-2-(1-(2,2,2-Trifluoro-ethanoyl)-piperidin-2-yl-methyl)-benzofuran-3-carbonitrile

To a solution of(RS)-1-(2-(3-bromo-benzofuran-2-ylmethyl-piperidin-1-yl)-2,2,2-trifluoro-ethanone,D41 (840 mg, 2.1 mmol) in N-methylpyrrolidinone (15 ml) was addedcopper(I)cyanide (387 mg, 4.2 mmol) and the mixture refluxed for 4.5 h.The reaction mixture was cooled and diluted with water (100 ml), 0.880ammonia (3 ml) and ethyl acetate (3×). The combined extracts were dried(Na₂SO₄) and the solvent removed in vacuo. The residual oil wasredissolved in ethyl acetate (75 ml) and washed with water (4×), brine,dried (Na₂SO₄) and the solvent removed in vacuo. Chromatography (silicagel) afforded the title compound as a solid.

Mass spectrum (Electrospray LC/MS): Found 337 (MH⁺). C₁₇H₁₅F₃N₂O₂requires 336.

DESCRIPTION 43 (RS)-Morpholin-3-yl-acetic acid ethyl ester

N-chloromorpholine (24 g) in diethyl ether (20 ml) was added drop-wiseover 2.5 h to a vigorously stirred solution of potassium hydroxide (22.1g, 0.37 mol) in ethanol (130 ml) at 90° C. Heating was continued at 80°C. for 2 h. After standing at room temperature for 48 h the mixture wasfiltered to remove the inorganics and the solvent removed from thefiltrate in vacuo. The residue was partitioned between diethyl ether andbrine, dried (Na₂SO₄) and the solvent removed in vacuo. The resultingbrown oil was dissolved in acetonitrile (100 ml). Triethylamine (25 ml)and monoethyl malonate (25 g) were added and the mixture heated at 16°C. for 16 h. The volatiles were removed in vacuo and the residuepartitioned between saturated aqueous potassium carbonate and diethylether. The organic phase was dried (Na₂SO₄) and the solvent removed invacuo to afford the title compound as a brown oil (3.5 g).

Mass Spectrum (API⁺): Found 174 (MH⁺). C₈H₁₅NO₃ requires 173.

DESCRIPTION 44(RS)-(4-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-morpholin-3-yl)-aceticacid ethyl ester

The title compound (1.48 g, 66%) was prepared from(RS)-morpholin-3-yl-acetic acid ethyl ester, D43 (1.37 g, 5.8 mmol) and5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (1.00 g, 5.8mmol) according to a procedure similar to that described for D16.

Mass spectrum (Electrospray LC/MS): Found 393 (MH⁺). C₁₉H₂₁FN₂O₄Srequires 392.

DESCRIPTION 45(RS)-(4-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-morpholin-3-yl)-aceticacid

The title compound (1.33 g, 99%) was prepared from(RS)-(4-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-morpholin-3-yl)-aceticacid ethyl ester, D44 (1.46 g, 3.7 mmol) according to a proceduresimilar to that described for D17.

Mass Spectrum (API⁺): Found 363 (M-H). C₁₇H₁₇FN₂O₄S requires 364.

DESCRIPTION 46(RS)-2-(1-Furo[3,2-b]pyridin-2-yl)methanoyl)piperidine-1-carboxylic acidtert-butyl ester

The title compound was prepared using the method of Description 10 fromfuro[3,2-b]pyridine (1.14 g, 9.6 mmol) (Shiotani and Morita, J. Het.Chem., 23, 665, 1986), as a pale yellow solid (1.97 g, 62%).

Mass Spectrum (API⁺): Found 331 (MH⁺). C₁₈H₂₂N₂O₄ requires 330.

DESCRIPTION 47 (RS)-2-Piperidin-2-ylmethyl-furo[3,2-b]pyridine

The title compound was prepared using the method of Description 3 from(RS)-2-(1-furo[3,2-b]pyridin-2-yl)methanoyl)piperidine-1-carboxylic acidtert-butyl ester, D46 (1.95 g, 5.9 mmol), as a pale green gum (0.75 g,59%).

Mass Spectrum (API⁺): Found 217 (MH⁺). C₁₃H₁₆N₂O requires 216.

DESCRIPTION 48(RS)-2-[1-(5-Fluorobenzofuran-2-yl)-methanoyl]-piperazine-1,4-dicarboxylicacid 1-benzyl ester 4-tert-butyl ester

The title compound was prepared from(RS)-2-(methoxymethylcarbamoyl)piperazine-1,4-dicarboxylic acid 1-benzylester 4-tert-butyl ester (1.25 g, 3.07 mmol) (WO01/00214) and5-fluorobenzofuran (0.42 g, 3.09 mmol) (WO99/51575) by the method ofDescription 2 as a pale green gum (0.81 g, 55%).

Mass spectrum (API⁺): Found 505 (MNa⁺). C₂₆H₂₇FN₂O₆ requires 482.

DESCRIPTION 49(RS)-2-[1-(5-Fluoro-benzofuran-2-yl)methanoyl]-piperazine-1-carboxylicacid benzyl ester

The title compound was prepared from(RS)-2-[1-(5-fluorobenzofuran-2-yl)-methanoyl]-piperazine-1,4-dicarboxylicacid 1-benzyl ester 4-tert-butyl ester, D48 (0.81 g, 1.68 mmol) by themethod of Description 52 as a pale yellow amorphous solid (0.57 g, 90%).

Mass spectrum (API⁺): Found 383 (MH⁺). C₂₁H₁₉FN₂O₄ requires 382.

DESCRIPTION 50(RS)-2-[1-(5-Fluoro-benzofuran-2-yl)methanoyl]-4-methyl-piperazine-1-carboxylicacid benzyl ester

97% Formic acid (0.19 g, 4 mmol) was added to a stirred mixture of(RS)-2-[1-(5-fluoro-benzofuran-2-yl)methanoyl]-piperazine-1-carboxylicacid benzyl ester, D49 (0.57 g, 1.5 mmol) in water (5 ml). Stirring wascontinued as a 37% formaldehyde solution in water (0.155 g) was added.The resultant mixture was heated at 100° C. for 3.5 h, cooled, dilutedwith water (30 ml) and basified with 2N sodium hydroxide. The mixturewas extracted with ethyl acetate (2×) and the combined extracts dried(Na₂SO₄) and the solvent removed in vacuo to afford the title compound(0.57 g, 96%).

Mass spectrum (API⁺): Found 397 (MH⁺). C₂₂H₂₁FN₂O₄ requires 396.

DESCRIPTION 51 (RS)-3-(5-Fluorobenzofuran-2-ylmethyl)-1-methylpiperazine

The title compound was prepared from(RS)-2-[1-(5-fluoro-benzofuran-2-yl)methanoyl]-4-methyl-piperazine-1-carboxylicacid benzyl ester, D50 using the method of Description 3 as a yellow gum(0.43 g).

Mass spectrum (API⁺): Found 249 (MH⁺). C₁₄H₁₇FN₂O require 248.

DESCRIPTION 52 (RS)-2-(Methoxy-methyl-carbamoyl)-piperazine-1-carboxylicacid benzyl ester

A mixture of(RS)-2-(methoxy-methyl-carbamoyl)-piperazine-1,4-dicarboxylic acid1-benzyl ester 4-tert-butyl ester (WO 01/00214) (5 g, 0.012 mol) indichloromethane (100 ml) and trifluoroacetic acid (20 ml) was heated at40° C. for 0.5 h, cooled and evaporated. The residual oil was dissolvedin dichloromethane (150 ml) and washed with 1M sodium hydroxide (80 ml).The aqueous phase was re-extracted with dichloromethane (2×) and thecombined extracts dried (Na₂SO₄) and the solvent removed in vacuo togive the title compound as an oil (3.6 g, 100%).

Mass spectrum (API⁺): Found 308 (MH⁺). C₁₅H₂₁N₃O₄ requires 307.

DESCRIPTION 53(RS)-2-(Methoxy-methyl-carbamoyl)-4-methyl-piperazine-1-carboxylic acidbenzyl ester

To (RS)-2-(methoxy-methyl-carbamoyl)-piperazine-1-carboxylic acid benzylester, D52 (3 g, 10 mmol) in 1,2-dichloroethane (50 ml) was addedformaldehyde (0.85 ml of 37% w/w solution in water, 11 mmol) and themixture stirred at ambient temperature for 0.75 h. Sodiumtriacetoxyborohydride (2.55 g, 12 mmol) was added portionwise over 0.25h, and the resulting mixture stirred at ambient temperature for 18 h.The reaction was partitioned between dichloromethane (300 ml) and 1Msodium hydroxide (100 ml). The aqueous was re-extracted withdichloromethane (250 ml) and the combined extracts dried (Na₂SO₄) andthe solvent removed in vacuo. The residue was chromatographed on silicagel eluting with ethyl acetate-hexane mixtures to afford the titleproduct (3 g, 96%) as a gum.

Mass spectrum (API⁺): Found 322. C₁₆H₂₃N₃O₄ requires 321.

DESCRIPTION 54(RS)-2-(Methoxy-methyl-carbamoyl)-4-methyl-piperazine-1-carboxylic aciddimethyl-ethyl ester

A mixture of(RS)-2-(Methoxy-methyl-carbamoyl)-4-methyl-piperazine-1-carboxylic acidbenzyl ester, D53 (2.9 g, 9 mmol) and di-tert-butyl dicarbonate (2.4 g,11 mmol) in ethyl acetate (180 ml) was hydrogenated at NTP over 10% Pd—C(1.45 g, 50% aqueous paste) for 64 h. The mixture was filtered throughkieselguhr, washed with ethyl acetate and the filtrate evaporated. Theresidue was chromatographed on silica gel eluting with ethylacetate-methanol mixtures to afford the title product as a white solid(2.9 g, 92%).

Mass spectrum (API⁺): Found 288 (MH⁺). C₁₃H₂₅N₃O₄ requires 287.

DESCRIPTION 55(RS)-2-(1-Benzofuran-2-yl-methanoyl)-4-methyl-piperazine-1-carboxylicacid tert-butyl ester

The title compound (1.81 g, 52%) was prepared from(RS)-2-(methoxy-methyl-carbamoyl)-4-methyl-piperazine-1-carboxylic aciddimethyl-ethyl ester, D54 (2.9 g, 10.1 mmol) and benzofuran (0.74 g,10.1 mol) using the method of Description 2.

Mass spectrum (API⁺): Found 345 (MH⁺). C₁₉H₂₄N₂O₄ requires 344.

DESCRIPTION 56 (RS)-3-Benzofuran-2-ylmethyl-1-methyl-piperazine

The title compound was obtained from(RS)-2-(1-benzofuran-2-yl-methanoyl)-4-methyl-piperazine-1-carboxylicacid tert-butyl ester, D55 (1.28 g, 3.7 mmol) using the method ofDescription 3 and was used without purification.

Mass spectrum (API⁺): Found 231 (MH⁺). C₁₄H₁₈N₂O require 230.

DESCRIPTION 57(RS)-1-(5-Fluoro-benzofuran-2-yl)-1-((RS)-4-methyl-piperazin-2-yl)-methanol

(RS)-2-[1-(5-Fluoro-benzofuran-2-yl)methanoyl]-4-methyl-piperazine-1-carboxylicacid benzyl ester, D50 (0.65 g, 1.6 mmol) in ethyl acetate (20 ml) andmethanol (20 ml) was hydrogenated at NTP over 10% Pd—C (0.47 g, 50% w/wpaste in water) for 3.5 h. The reaction mixture was filtered throughKieselguhr, washing well with methanol and the filtrate evaporated toafford the title product (0.41 g, 90%).

¹H NMR δ: 2.05 and 2.70 (together 2H, m), 2.12 and 2.62 (together 2H,m), 2.24 (3H, s), 2.94 and 3.12 (2H, m), 3.28 (1H, m), 4.84 (1H, d, J=6Hz), 6.69 (1H, s), 6.97 (1H, m), 7.19 (1H, dd, J=8 and 2 Hz), 7.36 (1H,dd, J=8 and 4 Hz).

Mass spectrum (API⁺): Found 265 (MH⁺). C₁₄H₁₇N₂O₂ require 264.

DESCRIPTION 58 (RS)-4-Fluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole

(RS)-2-Carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1.93g) was heated with 1,2-diamino-3-fluorobenzene (1.00 g) (Kirk, K. L, J.Org. Chem., 1969, 34, 384) as described in Description 18 to afford thetitle compound (1.14 g).

Mass Spectrum (API⁺): Found 234 (MH⁺). C₁₃H₁₆FN₃ requires 333.

DESCRIPTION 59(RS)-2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidine-1-carboxylicacid tert-butyl ester

A solution of(RS)-5,6-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole, D18 (1.5 g)in dichloromethane was treated with triethylamine (0.98 ml), thendi-tert-butyl dicarbonate (1.3 g). After stirring for 18 h at roomtemperature under argon the mixture was diluted with dichloromethanethen washed with HCl (2M). The aqueous phase was basified with solidK₂CO₃ and extracted with dichloromethane. The organic phase was washedwith aqueous NaHCO₃, brine and dried (MgSO₄). The solvent was removed invacuo to afford the title compound (2 g).

Mass Spectrum (API⁺): Found 352 (MH⁺). C₁₈H₂₃F₂N₃O₂ requires 351.

DESCRIPTION 60(RS)-2-(5,6-Difluoro-1-methyl-1H-benzoimidazol-2-ylmethyl)-piperidine-1-carboxylicacid tert-butyl ester

To a stirred suspension of sodium hydride (0.46 g, 60% dispersion inmineral oil) in dimethylformamide (30 ml) at 0° C., under argon, wasadded(RS)-2-(5,6-difluoro-1H-benzoimidazol-2-ylmethyl)-piperidine-1-carboxylicacid tert-butyl ester, D59 (2 g) and the reaction mixture stirred for afurther 30 min. before the addition of iodomethane (0.78 ml). Thereaction mixture was then stirred at room temperature for 18 h, afurther equivalent of iodomethane (0.35 ml) was added and stirringcontinued for 24 h. Further portions of sodium hydride (0.23 g, 60%dispersion in mineral oil) and iodomethane (0.35 ml) were added and thereaction stirred for an additional 24 h. After diluting with water, theaqueous layer was extracted with diethyl ether (3×). The combinedorganics were dried (MgSO₄) and solvent removed in vacuo to afford thetitle compound (0.5 g).

Mass Spectrum (Electrospray LC/MS): Found 266 (MH⁺—^(t)BOC).C₁₉H₂₅F₂N₃O₂ requires 365.

DESCRIPTION 61(RS)-5,6-Difluoro-1-methyl-2-piperidin-2-ylmethyl-1H-benzoimidazole

(RS)-2-(5,6-Difluoro-1-methyl-1H-benzoimidazol-2-ylmethyl)-piperidine-1-carboxylicacid tert-butyl ester, D60 (0.5 g) was treated with trifluoroacetic acid(5 ml) as described for Description 6 to afford the title compound(0.363 g)

Mass spectrum (Electrospray): Found 266 (MH⁺). C₁₄H₁₇F₂N₃ requires 265.

DESCRIPTION 62(RS)-2-[1-(5-Chloro-benzofuran-2-yl)-methanoyl]-4-methyl-piperazine-1-carboxylicacid tert-butyl ester

The title compound (0.98 g) was prepared from(RS)-2-(methoxy-methyl-carbamoyl)-4-methyl-piperazine-1-carboxylic aciddimethyl-ethyl ester, D54 (1.60 g) and 5-chloro-benzofuran (0.86 g,FP1.537.206) using the method of Description 2.

Mass Spectrum (Electrospray LC/MS): Found 279 (MH⁺—^(t)BOC). C₁₉H₂₃³⁵ClN₂O₄ requires 378.

DESCRIPTION 63 3-(5-Chloro-benzofuran-2-ylmethyl)-1-methyl-piperazine

The title compound (0.61 g) was prepared from(RS)-2-[1-(5-chloro-benzofuran-2-yl)-methanoyl]-4-methyl-piperazine-1-carboxylicacid tert-butyl ester, D62 (0.98 g) using the method of Description 3and used without purification.

Mass Spectrum (Electrospray LC/MS): Found 265 (MH⁺). C₁₄H₁₇ ³⁵ClN₂Orequires 264.

DESCRIPTION 64(RS)-2-[1-(5,7-Dichloro-benzofuran-2-yl)-methanoyl]-4-methyl-piperazine-1-carboxylicacid tert-butyl ester

The title compound (0.94 g) was prepared from(RS)-2-(methoxy-methyl-carbamoyl)-4-methyl-piperazine-1-carboxylic aciddimethyl-ethyl ester, D54 (1.00 g) and 5,7-dichloro-benzofuran (0.65 g,FP1.537.206) using the method of Description 2.

Mass Spectrum (Electrospray LC/MS): Found 413 (MH⁺). C₁₉H₂₂ ³⁵Cl₂N₂O₄requires 412.

DESCRIPTION 65(RS)-3-(5,7-Dichloro-benzofuran-2-ylmethyl)-1-methyl-piperazine

The title compound (0.53 g) was prepared from(RS)-2-[1-(5,7-dichloro-benzofuran-2-yl)-methanoyl]-4-methyl-piperazine-1-carboxylicacid tert-butyl ester, D64 (0.94 g) using the method of Description 3and used without purification.

Mass Spectrum (API⁺LC/MS): Found 299 (MH⁺). C₁₄H₁₆ ³⁵Cl₂N₂O requires298.

DESCRIPTION 66 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-indole

A stirring, ice-cooled solution of indole (5.86 g, 50 mmol) in DMF (130ml) under argon was treated with sodium hydride (3.3 g, 60% dispersionon mineral oil, 80 mmol) and the reaction mixture then stirred at roomtemperature for 45 min. After cooling to 0° C.2,2-(trimethylsilyl)ethoxymethyl chloride (12.5 g, 75 mmol) was addeddropwise. The reaction mixture was then stirred at room temperature for4 h. The DMF was removed in vacuo, the residue was poured into water andthe product was extracted with diethyl ether. The combined organics werewashed with brine, dried (Na₂SO₄) and the solvent removed in vacuo.Chromatography (silica gel, 0-20% diethyl ether-40-60 pet.ether)afforded the title compound (12.2 g, 100%).

¹HNMR δ: 0.00 (9H, s), 0.96 (2H, t, J=8 Hz), 3.53 (2H, t, J=8 Hz), 5.55(2H, s), 6.59 (1H, m), 7.20 (2H, m), 7.30 (1H, m with CHCl₃), 7.55 (1H,dd, J=1 and 8 Hz), 7.70 (1H, dd, J=1 and 8 Hz).

DESCRIPTION 67(RS)-2-{1-[1-(2-Trimethylsilanyl-ethoxymethyl)-1H-indol-2-yl]-methanoyl}-piperidine-1-carboxylicacid tert-butyl ester

A stirring, ice-cooled solution of1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole, D66 (742 mg, 3 mmol) inDME (5 ml) was treated drop-wise with n-butyl lithium (2.2 ml, 1.6M inhexanes, 3.5 mmol). The resulting green solution was stirred at 0-5° C.for 15 min. then was treated with(RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine,D1 (952 mg, 3.5 mmol) in DME (2.5 ml). After stirring at thistemperature for a further 45 min. saturated aqueous NH₄Cl was added (10ml) and the product was extracted with diethyl ether. The organics werecombined, the solvent removed in vacuo and the residue chromatographed(silica gel, 10% diethyl ether-pentane) to afford the title compound asa colourless oil (510 mg, 37%).

Mass Spectrum (API⁺): Found 359 (MH⁺—^(t)BOC). C₂₅H₃₈N₂O₄Si requires458.

DESCRIPTION 68(RS)-2-Piperidin-2-ylmethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole

The title compound (1.1 g) was prepared from(RS)-2-{1-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-2-yl]-methanoyl}-piperidine-1-carboxylicacid tert-butyl ester, D67 (1.9 g) according to a procedure similar tothat for Description 3 and used without purification.

DESCRIPTION 69(RS)-2-[1-(5-Bromo-benzofuran-2-yl)-methanoyl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound (0.96 g) was prepared from 5-bromo-benzofuran (3.6 g,prepared according to procedures similar to those described in Synth.Commun.,

257, (1989)) and(RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine,D1 (4.9 g) according to a procedure similar to that for Description 2.

Mass Spectrum (API⁺): Found 308 (MH⁺—^(t)BOC). C₁₉H₂₂ ⁷⁹BrNO₄ requires407.

DESCRIPTION 70 (RS)-2-(5-Bromo-benzofuran-2-ylmethyl)-piperidine

The title compound (0.53 g) was prepared from(RS)-2-[1-(5-bromo-benzofuran-2-yl)-methanoyl]-piperidine-1-carboxylicacid tert-butyl ester, D69 (1.00 g)

according to a procedure similar to that for Description 3 and usedwithout purification.

Mass Spectrum (API⁺): Found 294 (MH⁺). C₁₄H₁₆ ⁷⁹BrNO requires 293.

DESCRIPTION 71(RS)-2-[1-(4-Bromo-benzofuran-2-yl)-methanoyl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound (1.45 g) was prepared from 4-bromo-benzofuran (3.65g, WO0109111) and(RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine,D1 (5.17 g) according to a procedure similar to that for Description 2.

Mass Spectrum (API⁺): Found 308 (MH⁺—^(t)BOC). C₁₉H₂₂ ⁷⁹BrNO₄ requires407.

DESCRIPTION 72 (RS)-2-(4-Bromo-benzofuran-2-ylmethyl)-piperidine

The title compound (0.90 g) was prepared from(RS)-2-[1-(4-bromo-benzofuran-2-yl)-methanoyl]-piperidine-1-carboxylicacid tert-butyl ester, D71 (1.40 g) according to a procedure similar tothat for Description 3 and used without purification.

DESCRIPTION 73(RS)-2-[1-(3-Methyl-benzofuran-2-yl)-methanoyl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound (300 mg) was prepared from 3-methyl-benzofuran (390mg) and(RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine,D1 (820 mg) according to a procedure similar to that for Description 2.

Mass Spectrum (API⁺): Found 244 (MH⁺—^(t)BOC). C₂₀H₂₅NO₄ requires 343.

DESCRIPTION 74 (RS)-2-(3-Methyl-benzofuran-2-ylmethyl)-piperidine

The title compound (184 mg) was prepared from(RS)-2-[1-(3-methyl-benzofuran-2-yl)-methanoyl]-piperidine-1-carboxylicacid tert-butyl ester, D73 (300 mg) according to a procedure similar tothat for Description 3 and used without purification.

DESCRIPTION 752-[1-(4-Fluoro-benzofuran-2-yl)-methanoyl]-piperidine-1-carboxylicacid-tert-butyl ester

The title compound (500 mg) was prepared from 4-fluoro-benzofuran (450mg) and(RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine,D1 (900 mg) according to a procedure similar to that for Description 2.

Mass Spectrum (API⁺): Found 248 (MH⁺—^(t)BOC). C₁₉H₂₂FNO₄ requires 347.

DESCRIPTION 76 (RS)-2-(4-Fluoro-benzofuran-2-ylmethyl)-piperidine

The title compound (310 mg) was prepared from(RS)-2-[1-(4-fluoro-benzofuran-2-yl)-methanoyl]-piperidine-1-carboxylicacid tert-butyl ester, D75 (500 mg)

according to a procedure similar to that for Description 3 and usedwithout purification.

DESCRIPTION 77(RS)-2-[1-(4,6-Dichloro-benzofuran-2-yl)-methanoyl]-4-methyl-piperazine-1-carboxylicacid tert-butyl ester

The title compound (566 mg) was prepared from 4,6-dichloro-benzofuran(390 mg) and(RS)-1-(tert-butyloxycarbonyl)-2-1-methoxy-N-methylcarbamoyl)-piperidine,D1 (600 mg) according to a procedure similar to that for Description 2.

DESCRIPTION 78(RS)-3-(4,6-Dichloro-benzofuran-2-ylmethyl)-1-methyl-piperazine

The title compound (527 mg) was prepared from(RS)-2-[1-(4,6-dichloro-benzofuran-2-yl)-methanoyl]-4-methyl-piperazine-1-carboxylicacid tert-butyl ester, D77 (900 mg) according to a procedure similar tothat for Description 3 and used without purification.

Mass Spectrum (API⁺): Found 299 (MH⁺). C₁₄H₁₆ ³⁵Cl₂N₂O requires 298.

DESCRIPTION 79(RS)-2-(Methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acidtert-butyl ester

The title compound was prepared from (RS)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester (14.8 g) and N,O-dimethylhydroxylamine.HCl (7.37g) according to a procedure similar to that for Example 4.

Mass Spectrum (Electrospray LC/MS): Found 159 (MH⁺—^(t)BOC). C₁₂H₂₂N₂O₄requires 258.

DESCRIPTION 80(RS)-2-(1-Benzofuran-2-yl-methanoyl)-pyrrolidine-1-carboxylic acidtert-butyl ester

The title compound (2.7 g) was prepared from benzofuran (2.29 g) and(RS)-2-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acidtert-butyl ester, D79 (5.00 g) according to a procedure similar to thatfor Description 2.

Mass Spectrum (API⁺): Found 216 (MH⁺—^(t)BOC). C₁₈H₂₂₁NO₄ requires 315.

DESCRIPTION 81 (RS)-2-Benzofuran-2-ylmethyl-pyrrolidine

The title compound (0.57 g) was prepared from(RS)-2-(1-benzofuran-2-yl-methanoyl)-pyrrolidine-1-carboxylic acidtert-butyl ester, D80 (1.00 g) according to a procedure similar to thatfor Description 3 and used without purification.

DESCRIPTION 82(RS)-2-(1-Benzo[b]thiophen-2-yl-methanoyl)-piperidine-1-carboxylic acidtert-butyl ester

The title compound (1.60 g) was prepared from benzo[b]thiophene (0.80 g)and(RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine,D1 (1.62 g) according to a procedure similar to that for Description 2.

DESCRIPTION 83 (RS)-2-Benzo[b]thiophen-2-ylmethyl-piperidine

The title compound (410 mg) was prepared from(RS)-2-(1-benzo[b]thiophen-2-yl-methanoyl)-piperidine-1-carboxylic acidtert-butyl ester, D82 (666 mg)

according to a procedure similar to that for Description 3 and usedwithout purification.

EXAMPLE 1(RS)-2-(2-Benzofuranylmethyl)-1-((5-(4-fluorophenyl)-2-methyl-thiazol-4-yl)-carbonyl)-piperidine

5-(4-(Fluorophenyl)-2-methyl-thiazole-4-carbonyl chloride (136 mg, 0.53mmol) in dichloromethane (1 ml) was added to a solution of(RS)-2-(2-benzofuranylmethyl)piperidine (104 mg, 0.48 mmol) andtriethylamine (0.20 ml, 1.45 mmol) in dichloromethane (4 ml) and themixture shaken at ambient temperature for 30 min. The resultant waswashed with saturated aqueous sodium hydrogen carbonate (8 ml). Theorganic layer was applied directly onto a pre-packed silica gel columnand chromatographed eluting with ethyl acetate hexane mixtures to givethe title compound (50 mg, 24%) as an off-white solid.

Mass spectrum (API⁺): found 435 (MH⁺): C₂₅H₂₃FN₂O₂S requires 434.

EXAMPLE 2(RS)-1-(2-Benzooxazol-2-ylmethyl-piperidin-1-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

5-(4-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.05 g) indimethylformamide (2.5 ml) was treated sequentially withdiisopropylethylamine (0.12 ml),[O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate] (0.08 g) and the amine of Description 6 (0.047 g)in dimethylformamide (2.5 ml). The mixture was stirred for 16 h, dilutedwith ethyl acetate and the organic phase washed with water, dried(MgSO₄) and solvent removed at reduced pressure. The residue waschromatographed (silica gel, 0→30% ethyl acetate:pentane) to give thetitle compound (0.06 g)

Mass spectrum (API⁺): found 436 (MH⁺): C₂₄H₂₂FN₃O₂S requires 435.

EXAMPLE 3(RS)-1-(2-Benzooxazol-2-ylmethyl-piperidin-1-yl)-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone

The title compound (0.02 g) was prepared from the amine of Description 6(0.047 g) and 2-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoic acid (0.045 g)according to the method of Example 2.

Mass spectrum (API⁺): found 403 (MH⁺): C₂₃H₂₂N₄O₃ requires 402.

EXAMPLE 4(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-[4-(4-fluoro-phenyl)-1-methyl-1-H-pyrazol-3-yl]-methane

A mixture of (RS)-2-(2-benzofuranylmethyl)piperidine, D3 (0.108 g, 0.5mmol), 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (0.11g, 0.5 mmol), EDC.HCl (0.106 g, 0.55 mmol) and 1-hydroxybenzotriazole(0.01 g, 0.07 mmol) in dichloromethane (4 ml) was shaken for 20 h. Theresultant was washed with saturated aqueous sodium bicarbonate (8 ml)and the organic layer was added directly onto a dry 10 g prepackedsilica gel cartridge. Elution with 10-100% ethyl acetate in hexanegradient then 1-20% methanol in ethyl acetate gradient afforded thetitle compound as a colourless amorphous solid (0.059 g, 28%).

¹H NMR (CDCl₃) δ: 1.05-1.30 (1H, m), 1.35-1.80 (5H, m), 2.80-3.20 (3H,m), 3.53 (0.55H, broad m), 3.81 and 3.93 (3H, 2×s), 4.13 (0.45H, broadm), 4.74 (0.45H, broad m), 5.41 (0.55H, broad m), 6.26 and 6.60 (1H,2×s), 6.85 and 6.95 (2H, 2×t, J=8.6 Hz), 7.10-7.55 (7H, m).

Mass spectrum (Electrospray LC/MS): Found 418 (MH⁺). C₂₅H₂₄FN₃O₂requires 417.

The compounds of Examples 5-22 and 90-91 in Table 1 were prepared fromthe appropriate amine and acid using similar procedures to thatdescribed in Example 4. The compound of Example 13 was prepared as thehydrochloride salts.

TABLE 1

Ex- Mass Spectrum am- (Electrospray ple Ar² R LC/MS) 5

F Found MH⁺453. C₂₅H₂₂F₂N₂O₂S requires 452 6

F Found MH⁺422. C₂₃H₂₀FN₃O₂S requires 421 7

F Found MH⁺389. C₂₄H₂₁FN₂O₂ requires 388 8

F Found MH⁺389. C₂₄H₂₁FN₂O₂ requires 388 9

F Found MH⁺369. C₂₁H₂₁FN₂O₃ requires 368. 10

F Found MH⁺482. C₂₆H₂₅F₂N₃O₂S requires 481. 11

F Found MH⁺423. C₂₅H₂₇FN₂O₃ requires 422. 12

F Found MH⁺422. C₂₂H₁₉F₄NO₃ requires 421. 13

H Found MH⁺407. C₂₅H₃₀N₂O₃ requires 406 14

H Found MH⁺371. C₂₄H₂₂N₂O₂ requires 370. 15

H Found MH⁺398. C₂₅H₂₃N₃O₂ requires 397. 16

H Found MH⁺405. C₂₃H₂₁FN₄O₂ requires 404. 17

H Found MH⁺404. C₂₄H₂₂FN₃O₂ requires 403. 18

H Found MH⁺451. C₂₅H₂₃FN₂O₃S requires 450. 19

H Found MH⁺371. C₂₄H₂₂N₂O₃ requires 370 20

H Found MH⁺371. C₂₄H₂₂N₂O₂ requires 370. 21

H Found MH⁺518. C₃₀H₃₅N₃O₃S requires 517. 22

H Found MH⁺532. C₃₁H₃₇N₃O₃S requires 531. 90

H Found MH⁺447. C₂₆H₂₆N₂O₃S requires 446. (API LC/MS) 91

H Found MH⁺504. C₂₉H₃₃N₃O₃S requires 436.

EXAMPLE 23(RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-(2-furo[2,3-b]pyridin-2-ylmethyl-piperidin-1-yl)-methanone

The title compound was prepared, using the method of Example 4, from5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.171 g, 0.72mmol) and (RS)-2-piperidin-2-ylmethyl-furo[2,3-b]pyridine, D11 (0.13 g,0.60 mmol) as a colourless solid (0.129 g, 49%).

¹H NMR δ: 0.90-1.20 (1H, m), 1.30-1.85 (5H, m), 2.49 and 2.70 (3H, 2×s),2.80-3.20 (3H, m), 3.40 (0.45H, m), 4.10 (0.55H, m), 4.70 (0.55, m),5.35 (0.45H, m), 6.34 and 6.65 (1H, 2×s), 6.92 and 7.00 (2H, 2×t, J=8.6Hz), 7.15 (1H, m), 7.35-7.50 (2H, m), 7.80 (1H, m), 8.23 (1H, m).

Mass spectrum (Electrospray LC/MS): Found 436 (MH⁺). C₂₄H₂₂FN₃O₂Srequires 435.

EXAMPLE 24(RS)-1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazole-3-yl]-(2-furo[2,3-b]pyridin-2-ylmethyl-piperidin-1-yl)methanone

The title compound was prepared using the method of Example 4, from4-(4-(fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (0.159 g,0.72 mmol) and (RS)-2-piperidin-2-ylmethyl-furo[2,3-b]pyridine, D11(0.13 g, 0.60 mmol) as a colourless solid (0.12 g, 48%).

Mass Spectrum (Electrospray LC/MS): Found 419 (MH⁺). C₂₄H₂₃FN₄O₂requires 418.

EXAMPLE 25(RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-(2-quinolin-2-ylmethyl-piperidin-1-yl)-methanone

The title compound was prepared, using the method of Example 1, from5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (0.09 g, 0.35mmol) and 2-piperidin-2-ylmethyl-quinoline, D13 (0.053 g, 0.23 mmol) asa colourless solid (0.038 g, 37%).

¹H NMR (DMSO-d₆) δ: 1.00-1.90 (6H, m), 2.37 and 2.66 (3H, 2×s),2.90-3.30 (3.5H, m), 4.15 (0.5H, m), 4.45 (0.5H, m), 5.25 (0.5H, m),7.05 (2H, m), 7.10-7.85 (6H, m), 7.90 (1H, m), 8.05-8.30 (1H, 2×d, J=8.4Hz).

Mass spectrum (Electrospray LC/MS): Found 446 (MH⁺). C₂₆H₂₄FN₃OSrequires 445.

EXAMPLE 26(RS)-1-Benzofuran-2-yl-1-(1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-yl)-methanone

The title compound was prepared, using the method of Example 1, from5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (0.1 g, 0.39mmol) and (RS)-1-benzofuran-2-yl-1-piperidin-2-yl-methanone, D9 (0.1 g,0.43 mmol) as a colourless solid (0.074 g, 43%)

Mass spectrum (Electrospray LC/MS): Found 449 (MH⁺). C₂₅H₂₁FN₂O₃Srequires 448.

EXAMPLE 27(RS)-1-[2-(1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

(RS)-(1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-yl)-aceticacid, D17 (110 mg, 0.3 mmol) and benzene-1,2-diamine (33 mg, 0.3 mmol)in PPA (2 g) were heated at 140° C. for 3.5 h. The cooled reactionmixture was poured onto a mixture of crushed ice and K₂CO₃. The basicaqueous solution was extracted with ethyl acetate (3×). The combinedorganics were washed with brine, dried (MgSO₄) and the solvent removedin vacuo. Chromatography (silica gel, ethyl acetate) afforded the titlecompound as a dark yellow gum (72 mg, 52%).

Mass Spectrum (Electrospray LC/MS): Found 435 (MH⁺). C₂₄H₂₃FN₄OSrequires 434.

The compounds of the Examples 28-34 in Table 2 below were prepared fromthe appropriate benzene-1,2-diamine and(RS)-(1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-yl)-aceticacid, D17 using similar procedures to that described in Example 27.

TABLE 2

Example X Mass Spectrum (Electrospray LC/MS) 28 5-Cl Found MH⁺469.C₂₄H₂₂ ³⁵ClFN₄OS requires 468. 29 5-F Found MH⁺453. C₂₄H₂₂F₂N₄OSrequires 452. 30 5-Cl, 6-F Found MH⁺487. C₂₄H₂₁ ³⁵ClF₂N₄OS requires 486.31 4-Me Found MH⁺449. C₂₅H₂₅FN₄OS requires 448. 32 4,6-di-F FoundMH⁺471. C₂₄H₂₁F₃N₄OS requires 470. 33 4-CH₂NMe₂ Found MH⁺492.C₂₇H₃₀FN₅OS requires 491. 34 5-Br Found MH⁺513. C₂₄H₂₂ ⁷⁹BrFN₄OSrequires 512.

EXAMPLE 35(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

A solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid(700 mg, 3.0 mmol), HATU (1.12 g, 3.0 mmol) andN,N-diisopropylethylamine (1.54 ml, 9.0 mmol) in DMF (20 ml) was stirredat room temperature under argon for 2 min. The mixture was then treatedwith (RS)-5,6-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole, D18(742 mg, 3.0 mmol) and stirring was continued for 16 h. The solvent wasremoved in vacuo and the residue partitioned between water and ethylacetate. The organic phase was dried (Na₂SO₄) and the solvent removed invacuo. Chromatography (silica gel, 0-5% methanol-ethyl acetate) affordedthe title compound as a pale yellow solid (1.35 g, 97%).

Mass spectrum (Electrospray LC/MS): Found 471 (MH⁺). C₂₄H₂₁F₃N₄OSrequires 470

¹H NMR δ: 0.80-1.90 (6H+H₂O, bm), 2.71 and 2.75 (3H, 2×s), 3.04 (1H, dt,J=3 and 13 Hz), 3.17 (0.8H, dd, J=5 and 13 Hz), 3.42-3.58 (1.8H, bm),3.74 (0.2H, m), 4.43 (0.4H, m), 5.35 (1H, 0.8H, m), 6.75 (1.6H, t, J=8Hz), 7.00-7.20 (3H, bm), 7.40-7.57 (1.4H, m), 11.30 and 12.38 (1H,2×bs).

The title compound (900 mg) was dissolved in methanol and treated with1M HCl in diethyl ether (excess). The volatiles were removed in vacuoand the residue was triturated with ethyl acetate to give a white solid(805 mg). A sample (450 mg) was crystallised form ethyl acetate to givethe hydrochloride salt of the title compound as white solid (420 mg).

Mass spectrum (Electrospray LC/MS) Found 471. C₂₄H₂₁F₃N₄OS requires 470.

EXAMPLE 36(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

A solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid(1.00 g, 4.2 mmol), HATU (1.60 g, 4.2 mmol) andN,N-diisopropylethylamine (2.00 ml, 11.6 mmol) in DMF (20 ml) wasstirred at room temperature under argon for 2 min. The mixture was thentreated with (RS)-4,5-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole,D21 (1.06 g, 4.2 mmol) and stirring was continued for 16 h. The solventwas removed in vacuo and the residue was washed with water then wastriturated with ethyl acetate to afford the title compound as anoff-white solid (1.68 g, 85%).

Mass spectrum (Electrospray LC/MS): Found 471 (MH⁺). C₂₄H₂₁F₃N₄OSrequires 470.

The title compound (650 mg) was dissolved in methanol and treated with1M HCl in diethyl ether (excess). The volatiles were removed in vacuoand the residue was triturated with ethyl acetate to afford thehydrochloride salt of the title compound as a white solid (615 mg). Massspectrum (Electrospray LC/MS) Found 471 (MH⁺). C₂₄H₂₁F₃N₄OS requires470.

EXAMPLE 37(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone

A stirring solution of5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazole-4-carboxylic acid (632 mg,2.0 mmol, 80% pure), EDC.HCl (311 mg, 2.0 mmol) and1-hydroxybenzotriazole (270 mg, 2.0 mmol) in DMF (20 ml) was treatedwith (RS)-5,6-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole, D18(500 mg, 2.0 mmol). The reaction mixture was stirred at roomtemperature, under argon for 16 h. The DMF was removed in vacuo and theresidue was partitioned between ethyl acetate and water. The organicphase was dried (Na₂SO₄) and the solvent removed in vacuo.Chromatography (silica gel, 0-10% methanol-ethyl acetate) afforded thetitle compound as a pale yellow solid (350 mg, 36%).

Mass spectrum (Electrospray LC/MS): Found 487 (MH⁺). C₂₄H₂₁F₃N₄O₂Srequires 486.

¹H NMR (DMSO-d₆) δ: 0.90-1.80 (6H, bm), 2.92-3.30 (3H+DMSO, bm), 4.15(0.4H, m), 4.40-4.60 (1H, bm), 4.73 (1H, d, J=9 Hz), 5.30 (0.6H, m),6.20 (1H, m), 7.05-7.65 (6H, bm), 12.24 and 12.56 (1H, 2×bs).

The title compound (350 mg) was dissolved in methanol and treated with1M HCl in diethyl ether (excess). The volatiles were removed in vacuoand the residue was triturated with EtOAc to afford the hydrochloridesalt of the title compound as a white solid (215 mg). Mass spectrum(Electrospray LC/MS) Found 487 (MH⁺). C₂₄H₂₁F₃N₄O₂S requires 486.

EXAMPLE 38(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone

A stirring solution of5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazole-4-carboxylic acid (320 mg,1.0 mmol, 80% pure) and(RS)-4,5-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole, D21 (250 mg,1.0 mmol) in DMF (10 ml) was treated with EDC.HCl (194 mg, 1.0 mmol) and1-hydroxybenzotriazole (50 mg, 0.4 mmol). The reaction mixture wasstirred at room temperature, under argon for 16 h. The resultingsolution was diluted with diethyl ether then washed with saturatedaqueous NaHCO₃, water (3×) and brine. Drying (MgSO₄) and removal of thesolvent in vacuo afforded an orange gum. Chromatography (silica gel,0-2% methanol-dichloromethane) afforded the title compound as an orangepowder (160 mg, 33%). Mass spectrum (Electrospray LC/MS) Found 487(MH⁺). C₂₄H₂₁F₃N₄O₂S requires 486.

The title compound (80 mg) was dissolved in methanol and treated with 1MHCl in diethyl ether (excess). The volatiles were removed in vacuo andthe residue was triturated with diethyl ether to afford thehydrochloride salt of the title compound as a pale orange solid (65 mg).

Mass spectrum (Electrospray LC/MS): Found 487 (MH⁺). C₂₄H₂₁F₃N₄O₂Srequires 486.

EXAMPLE 39(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone

A solution of 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid(73 mg, 0.33 mmol), HATU (124 mg, 0.33 mmol) andN,N-diisopropylethylamine (0.35 ml) in DMF (6 ml) was stirred at roomtemperature under argon for 0.5 h. The mixture was then treated with(RS)-5,6-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole.2HCl, D₂₀(105 mg, 0.33 mmol) and stirring, under argon was continued for 16 h.The reaction mixture was diluted with diethyl ether and washed withwater (3×), dried (MgSO₄) and the solvent removed in vacuo.Chromatography (silica gel, ethyl acetate) afforded the title compound(88 mg, 57%).

Mass spectrum (Electrospray LC/MS): Found 454 (MH⁺). C₂₄H₂₂F₃N₅Orequires 453.

EXAMPLE 40(RS)-1-[2-(5-Methoxy-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

A stirring mixture of(1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-yl)-aceticacid, D17 (150 mg, 0.42 mmol) and 4-methoxy-benzene-1,2-diamine (58 mg,0.42 mmol) was heated at 120° C. for 4 h. The cooled reaction mixturewas dissolved in ethyl acetate, washed with sodium hydrogen carbonate(2×) then brine. The solvent was removed in vacuo and the residue waschromatographed (silica gel, ethyl acetate) to afford the title compoundas a brown gum (25 mg, 13%).

Mass spectrum (Electrospray LC/MS): Found 465 (MH⁺). C₂₅H₂₅FN₄O₂Srequires 464.

The compounds of the Examples 41-50 and 92-108 were prepared from theappropriate carboxylic acid or acid chloride and(RS)-4,5-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole, D21 using asimilar procedure to that described in Example 2 or a procedure similarto that described in Examples 1 or 4. The compounds of Examples 47, 48and 49 were converted to hydrochloride salts by treatment with 1M HCl indiethyl ether. The compound of Example 96 was prepared as thetrifluoroacetate salt.

TABLE 3

Mass Spectrum Exam- (Electrospray ple Ar² Method LC/MS) 41

E2 Found MH⁺453. C₂₄H₂₂F₂N₄OS requires 452. 42

E2 Found MH⁺454. C₂₄H₂₂F₃N₅O requires 453. 43

E2 Found MH⁺440. C₂₃H₂₀F₃N₅O requires 439. 44

E2 Found MH⁺540. C₂₈H₃₁F₂N₅O₂S requires 539. 45

E4 Found MH⁺471. C₂₄H₂₁F₃N₄OS requires 470. 46

E4 Found MH⁺471. C₂₄H₂₁F₃N₄OS requires 470. 47

E2 Found MH⁺440. C₂₁H₁₈F₅N₃O₂ requires 439. 48

E2 Found MH⁺400. C₂₂H₂₃F₂N₃O₂ requires 399. 49

E2 Found MH⁺416. C₂₂H₂₃F₂N₃O requires 415. 50

E2 Found MH⁺422. C₂₃H₂₁F₂N₅O requires 421. 92

E2 Found MH⁺437. C₂₄H₂₂F₂N₄O₂ requires 436. 93

E2 Found MH⁺505. C₂₄H₂₀ ³⁵Cl₂F₂N₄O₂ requires 504. 94

E2 Found MH⁺454. C₂₄H₂₂F₃N₅O requires 453. 95

E1 Found MH⁺489. C₂₄H₂₀ ³⁵ClF₃N₄O₂ requires 488. 96

E2 Found MH⁺471. C₂₄H₂₁ ³⁵ClF₂N₄O₂ requires 470. 97

E2 Found MH⁺414. C₂₃H₂₅F₂N₃O₂ requires 413. 98

E2 Found MH⁺414. C₂₃H₂₅F₂N₃O₂ requires 413. 99

E2 Found MH⁺462. C₂₇H₂₅F₂N₃O₂ requires 461. 100

E2 Found MH⁺430. C₂₃H₂₅F₂N₃O₃ requires 429. 101

E2 Found MH⁺414. C₂₃H₂₅F₂N₃O₂ requires 413. 102

E2 Found MH⁺444. C₂₄H₂₇F₂N₃O₃ requires 443. 103

E2 Found MH⁺442. C₂₄H₂₅F₂N₃O₃ requires 441. 104

E2 Found MH⁺450. C₂₆H₂₅F₂N₃O₂ requires 449. 105

E2 Found MH⁺433. C₂₅H₂₂F₂N₄O requires 432. 106

E2 Found MH⁺421. C₂₄H₂₂F₂N₄O requires 420. 107

E2 Found MH⁺554. C₂₉H₃₃F₂N₅O₂S requires 553. 108

E2 Found MH⁺568. C₃₀H₃₅F₂N₅O₂S requires 567.

The compounds of the Examples 51-55 and 109-112 in Table 4 were preparedfrom the appropriate carboxylic acid and(RS)-5,6-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole, D18 using asimilar procedure to that described in Example 2 or Example 4 or fromthe appropriate acid chloride and(RS)-5,6-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole, D18 using aprocedure similar to that described for Example 1. The compound ofExample 55 was converted to the hydrochloride salt by treatment with 1MHCl in diethyl ether. The compound of Example 109 was prepared as thetrifluoroacetate salt.

TABLE 4

Mass Spectrum (Electrospray Example Ar² Method LC/MS) 51

E2 Found MH⁺440. C₂₃H₂₀F₃N₅O requires 439. 52

E2 Found MH⁺438. C₂₃H₂₁F₂N₅O₂ requires 437 53

E2 Found MH⁺511. C₂₇H₂₉F₃N₆O requires 510 54

E2 Found MH⁺455. C₂₃H₂₁F₃N₆O requires 454 55

E1 Found MH⁺539. C₂₉H₃₂F₂N₄O₂S requires 538. 109

E4 Found MH⁺487. C₂₄H₂₁F₃N₄O₂S requires 486. 110

E2 Found MH⁺485. C₂₅H₂₃F₃N₄OS requires 484. 111

E4 Found MH⁺471. C₂₄H₂₁F₃N₄OS requires 470. 112

E4 Found MH⁺471. C₂₄H₂₁F₃N₄OS requires 470.

EXAMPLE 56(RS)-1-[2-(5,6-Difluoro-1-methyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone,E35 (400 mg, 0.85 mmol) was slowly added to an ice-cooled slurry of NaH(68 mg, 60% dispersion on mineral oil, 1.7 mmol) in DMF (10 ml). After0.5 h iodomethane (0.90 mmol) was added. The reaction mixture wasstirred at room temperature, under argon for 16 h. 2N HCl (9 drops) thenwater (100 ml) were added. The aqueous phase was extracted with EtOAc(2×) and the combined organics washed with brine, dried (Na₂SO₄) and thesolvent removed in vacuo. The residue was chromatographed (silica gel,50-100% pentane-ethyl acetate). Residual DMF was removed by dissolvingin ethyl acetate/diethyl ether and washing with water (2×). Drying(Na₂SO₄) and removal of the solvent in vacuo afforded the title compoundas a pale yellow solid (142 mg, 34%).

Mass spectrum (Electrospray LC/MS): Found 485 (MH⁺). C₂₅H₂₃F₃N₄OSrequires 484.

EXAMPLE 571-[(S)-2-(1H-Benzoimidazol-2-ylmethyl)-pyrrolidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound was prepared from(S)-pyrrolidin-2-ylmethyl-1H-benzoimidazole, D26 and5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid by a proceduresimilar to that described for Example 2. Chromatography (silica gel,0-8%[10% 0.880 NH₃ in MeOH] in dichloromethane) afforded the titlecompound as a brown gum.

Mass spectrum (API⁺): found 421 (MH⁺). C₂₃H₂₁N₄OS requires 420.

EXAMPLE 581-[(S)-2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-pyrrolidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound was prepared from,(S)-5,6-difluoro-pyrrolidin-2-ylmethyl-1H-benzoimidazole, D27 and5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid by a proceduresimilar to that described for Example 1. Chromatography (silica gel,0-8%[10% 0.880 NH₃ in methanol] in dichloromethane) afforded the titlecompound as a beige solid.

Mass spectrum (API⁺): found 457 (MH⁺). C₂₃H₁₉F₃N₄OS requires 456.

EXAMPLE 591-[(S)-2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-pyrrolidin-1-yl]-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]methanone

The title compound was prepared from,(S)-5,6-difluoro-pyrrolidin-2-ylmethyl-1H-benzoimidazole, D27 and4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid by aprocedure similar to that described for Example 2. Chromatography(silica gel, 0→8%[10% 0.880 NH₃ in methanol] in dichloromethane)afforded the title compound as a beige solid.

Mass spectrum (API⁺): found 440 (MH⁺): C₂₃H₂₀F₃N₅O requires 439.

EXAMPLE 60(RS)-1-(2-Benzothiazol-2-ylmethylpiperidin-1-yl)-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]-methanone

2-Piperidin-2-ylmethylbenzothiazole, D30 (0.135 g), HATU (0.228 g),diisopropylethylamine (0.300 ml) and5-(4-fluorophenyl)-2-methylthiazol-4-carboxylic acid (0.144 g) weredissolved in dry DMF and shaken at room temperature for 16 hours. Thesolvent was then evaporated and the residue partitioned betweendichloromethane and brine. The organic layer was dried (MgSO₄),evaporated and the residue chromatographed over silica gel. Elution withdiethyl ether provided the title compound as a foam (220 mg).

Mass spectrum (API⁺): found 452 (MH⁺): C₂₄H₂₂FN₃OS₂ requires 451.

EXAMPLE 61(RS)-1-(2-Benzothiazol-2-ylmethylpiperidin-1-yl)-1-[4-(4-fluorophenyl)-1-methyl-1-H-pyrazol-3-yl]-methanone

The title compound (0.210 g) was prepared from2-piperidin-2-ylmethyl-benzothiazole, D30 (0.135 g) and4-(4-fluorophenyl)-1-methyl-1-H-pyrazol-3-carboxylic acid (0.135 g)using the procedure described in Example 60.

Mass spectrum (API⁺): found 435 (MH⁺): C₂₄H₂₃FN₄OS requires 434.

EXAMPLE 62(RS)-1-(2-Benzothiazol-2-ylmethylpiperidin-1-yl)-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)phenyl]-methanone

The title compound (0.170 g) was prepared from2-piperidin-2-ylmethyl-benzothiazole, D30 (0.135 g), and2-(3-methyl-[1,2,4]oxadiazol-5-yl)benzoic acid (0.126 g) using theprocedure described in Example 60.

Mass spectrum (API⁺): found 419 (MH⁺): C₂₃H₂₂N₄O₂S requires 418.

EXAMPLE 63 AND EXAMPLE 64(RS)-1-[5-(4-Fluorophenyl)-2-methylthiazol-4-yl]-1-[2-(5,6,7,8-tetrahydro-[1,2,4]-triazolo[1,5-a]pyridin-2-ylmethyl)-piperidin-1-yl]-methanoneand(RS)-1-[5-(4-Fluorophenyl)-2-methylthiazol-4-yl]-1-(2-[1,2,4]triazolo[1,5-a]pyridin-2-ylmethylpiperidin-1-yl)-methanone

The mixture of2-piperidin-2-ylmethyl-5,6,7,8-tetrahydro-[1,2,4]-triazolo[1,5-a]pyridineand 2-piperidin-2-ylmethyl-[1,2,4]-triazolo[1,5-a]pyridine, D34 (0.220g) was treated with HATU (0.380 g), N,N-diisopropylethylamine (1.0 ml)and 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (0.240 g) indry DMF, according to the procedure described in Example 60. The crudeproduct was chromatographed (silica gel, 4% methanol-diethyl ether) toafford1-[5-(4-fluoro-phenyl)-2-methylthiazol-4-yl]-1-(2-[1,2,4]-triazolo[1,5-a]pyridin-2-ylmethylpiperidin-1-yl)-methanoneas a colourless foam (0.070 g) (Mass spectrum (API⁺): found 436 (MH⁺):C₂₃H₂₂FN₅OS requires 435). Continued elution (10% methanol-diethylether) afforded1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(5,6,7,8-tetrahydro-[1,2,4]-triazolo[1,5-a]pyridin-2-ylmethyl)-piperidin-1-yl]-methanoneas a colourless foam (0.230 g) (Mass spectrum (API⁺): found 440 (MH⁺):C₂₃H₂₆FN₅OS requires 439).

EXAMPLE 65a AND b1-[(RS)-2-((RS)-2-Benzofuran-2-yl-2-hydroxy-ethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone(as separate diastereoisomers)

A solution of(RS)-1-Benzofuran-2-yl-2-(1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-yl)-ethanone,D38 (50 mg, 0.11 mmol) in methanol was treated with sodium borohydride(50 mg). The reaction mixture was stirred at room temperature, underargon for 16 h. The volatiles were removed in vacuo and the residue wastriturated with dichloromethane. The dichloromethane soluble materialwas chromatographed (silica gel, diethyl ether) to afford, separatelythe two diastereoisomers of the title compound.

Mass spectrum (API⁺): found 447 (MH⁺—H₂O): C₂₆H₂₅FN₂O₃S requires 464(first eluting diastereoisomer).

Mass spectrum (API⁺): found 447 (MH⁺—H₂O): C₂₆H₂₅FN₂O₃S requires 464(second eluting diastereoisomer)

EXAMPLE 66(RS)-1-[2-(4-Bromo-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone

2-Methyl-5-(4-fluorophenyl)thiazole-4-carbonyl chloride (383 mg, 1.5mmol) was added portionwise over 5 min. to a stirred solution of(RS)-4-bromo-2-piperidin-2-ylmethyl-1H-benzoimidazole, D39 (400 mg, 1.4mmol) and triethylamine (0.57 ml, 5.0 mmol) in dichloromethane (20 ml)at room temperature. After 20 h the mixture was washed with saturatedsodium hydrogen carbonate. The organic layer was dried (Na₂SO₄) and thesolvent removed in vacuo. Chromatography (silica gel, 10-100% ethylacetate-hexane then 1-10% methanol-ethyl acetate) afforded the titlecompound as a pale brown amorphous solid (620 mg, 89%).

Mass spectrum (Electrospray LC/MS): Found 513 (MH⁺). C₂₄H₂₂ ⁷⁹BrFN₄OSrequires 512.

EXAMPLE 67(RS)-1-[2-(4-Cyano-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone

A mixture of(RS)-1-[2-(4-bromo-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone,E66 (216 mg, 0.42 mmol) and copper(I)cyanide (76 mg, 0.84 mmol) inN-methylpyrrolidinone (15 ml) was heated at reflux for 3 h. The reactionmixture was cooled, poured into water and extracted with ethyl acetate(2×). Solid sodium chloride was added to the aqueous layer which wasfurther extracted with ethyl acetate (2×). The combined organic extractswere washed with brine, dried (Na₂SO₄) and the solvent removed in vacuo.The residue was Chromatographed (silica gel, 10-100% ethylacetate-hexane then 1-20% methanol-ethyl acetate). Further purificationby HPLC (Supercosil ABZ⁺, 5-95% acetonitrile containing 0.1%trifluoroacetic acid-water containing 0.1% trifluoroacetic acid)afforded the title compound as a pale brown amorphous solid (5.3 mg,3%).

Mass spectrum (Electrospray LC/MS): Found 460 (MH⁺). C₂₅H₂₂FN₅OSrequires 459.

EXAMPLE 68(RS)-1-[2-(4-Acetyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone

To a deoxygenated solution of(RS)-1-[2-(4-bromo-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone,E66 (200 mg, 0.39 mmol) in anhydrous 1,4-dioxane (10 ml) was addedtributyl(1-ethoxyvinyl)tin (155 mg, 0.43 mmol) andtetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol). Theresultant mixture was refluxed under argon for 20 h. Furthertetrakis(triphenylphosphine)palladium(0) (60 mg, 0.052 mmol) was addedand refluxing continued for a further 24 h. On cooling, water (15 ml)and 5N hydrochloric acid (10 drops) were added and the mixture stirredat room temperature for 2 h. The reaction mixture was poured into waterand extracted with ethyl acetate (3×). The combined organics were dried(Na₂SO₄) and the solvent removed in vacuo. Chromatography (silica gel,

0-100% ethyl acetate-hexane then 2-5% methanol-ethyl acetate) affordedthe title compound as a pale orange solid (62 mg, 33%).

Mass spectrum (Electrospray LC/MS): Found 475 (M-H). C₂₆H₂₅FN₄O₂Srequires 476.

EXAMPLE 69(RS)-2-(1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-ylmethyl)-1H-benzoimidazole-5-carbonitrile

A stirring mixture of(RS)-1-[2-(5-bromo-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone,E34 (25 mg, 0.44 mmol) and copper(I)cyanide (79 mg, 0.88 mmol) inN-methylpyrrolidinone (7 ml) under argon was heated at 200° C. for 5 h.The cooled reaction mixture was diluted with water/ethyl acetate andfiltered through Kieselghur. The organic phase was washed with water(2×), brine (2×), dried (MgSO₄) and the solvent removed in vacuo. Theresidue was chromatograped (silica gel, 0-4% methanol (containing 10%.0.880 ammonia)-dichloromethane). Further purification by HPLC(Supercosil ABZ⁺, 5-95% acetonitrile containing 0.1% trifluoroaceticacid-water containing 0.1% trifluoroacetic acid) afforded the titlecompound as a pale brown gum (2 mg, 1%).

Mass spectrum (Electrospray LC/MS): Found 460 (MH⁺). C₂₅H₂₂FN₅OSrequires 459.

EXAMPLE 70(RS)-1-[2-(5,6-Difluoro-1-propyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone,E35 (150 mg, 0.32 mmol) was added slowly to an ice-cooled slurry ofsodium hydride (26 mg, 0.64 mmol, 60% dispersion in mineral oil) in DMF(10 ml). After stirring for a further 0.5 h, 1-iodopropane (60 mg, 0.35mmol) was added. The mixture was stirred at room temperature for 16 hthen partitioned between water and ethyl acetate. The organic phase waswashed with water, brine, dried (Na₂SO₄) and the solvent removed invacuo. Chromatography (silica gel, 50-100% ethyl acetate-pentane then0-5% methanol-ethyl acetate) afforded the title compound as a whitesolid.

Mass spectrum (Electrospray LC/MS): Found 513 (MH⁺). C₂₇H₂₇F₃N₄OSrequires 512.

The product was dissolved in methanol and treated with 1M HCl in diethylether (excess). The volatiles were removed in vacuo to afford thehydrochloride salt of the title compound as pale green solid (170 mg).

Mass spectrum (Electrospray LC/MS): Found 513. C₂₇H₂₇F₃N₄OS requires512.

EXAMPLE 71(RS)-1-{2-[5,6-Difluoro-1-(2-methoxy-ethyl)-1H-benzoimidazol-2-ylmethyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone,E35 (300 mg, 0.64 mmol) was added slowly to an ice-cooled slurry ofsodium hydride (51 mg, 1.3 mmol, 60% dispersion in mineral oil) in DMF(10 ml). After stirring for 0.5 h 1-bromo-2-methoxy-ethane (139 mg, 10mmol), N,N-diisopropylethylamine (0.3 ml) and potassium iodide (5 mg)was added. The mixture was stirred at room temperature for 0.5 h then100° C. for 16 h. The volatiles were removed in vacuo from the cooledreaction mixture. The residue was partitioned between ethyl acetate andwater. The aqueous phase was extracted with ethyl acetate (2×). Thecombined organics were dried (Na₂SO₄) and the solvent removed in vacuo.The residue was triturated with ethyl acetate to afford the titlecompound as a solid (306 mg, 65%).

Mass spectrum (Electrospray LC/MS) Found 529 (MH⁺). C₂₇H₂₇F₃N₄O₂Srequires 528.

The product was dissolved in methanol and treated with 1M HCl in diethylether (excess). The volatiles were removed in vacuo and the residuetriturated with methanol-ethyl acetate to afford the hydrochloride saltof the title compound as a white solid (66 mg).

Mass spectrum (Electrospray LC/MS): Found 529 (MH⁺). C₂₇H₂₇F₃N₄O₂Srequires 528.

EXAMPLE 72(RS)-1-{2-[1-(2-Dimethylamino-ethyl)-5,6-difluoro-1H-benzoimidazol-2-ylmethyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound was prepared from(RS)-1-[2-(5,6-difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone,E35 (300 mg) and (2-chloro-ethyl)-dimethyl-amine, according to aprocedure similar to that described for Example 71 as a white solid (88mg, 26%).

Mass spectrum (Electrospray LC/MS): Found 542 (MH⁺). C₂₈H₃₀F₃N₅OSrequires 541. The hydrochloride salt of the title compound was preparedas described for E71

Mass spectrum (Electrospray LC/MS): Found 542 (MH⁺). C₂₈H₃₀F₃N₅OSrequires 541.

EXAMPLE 73(RS)-1-{2-[5,6-difluoro-1-(2-hydroxy-ethyl)-1H-benzoimidazol-2-ylmethyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone,E35 (250 mg, 0.53 mmol) was added slowly to an ice-cooled slurry ofsodium hydride (43 mg, 1.1 mmol, 60% dispersion in mineral oil) in DMF(10 ml), under argon. After stirring for a further 0.5 h, 2-bromoethanol(0.045 ml, 0.64 mmol) was added. The mixture was heated at 110° C. for48 h, but only a minor amount of product had formed (MS). Potassiumcarbonate (1.00 g), N,N-diisopropylethylamine (1.0 ml) and a furtherportion of 2-bromoethanol (0.5 ml) were added and heating was continuedfor 16 h. The volatiles were removed in vacuo from the cooled reactionmixture. The residue was partitioned between ethyl acetate and water.The organic phase was dried (Na₂SO₄) and the solvent removed in vacuo.Chromatography (silica gel, 0-5% methanol-ethyl acetate) afforded thetitle compound as a white solid (78 mg, 29%).

Mass spectrum (Electrospray LC/MS): Found 515 (MH⁺). C₂₆H₂₅F₃N₄O₂Srequires 514.

EXAMPLE 74 AND EXAMPLE 75(RS)-1-[2-(6,7-Difluoro-1-methyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methyl-thiazol-4-yl]-methanoneand(RS)-1-[2-(4,5-Difluoro-1-methyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methyl-thiazol-4-yl]-methanone

(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone,E36 (400 mg, 0.85 mmol) was added slowly to an ice-cooled slurry ofsodium hydride (68 mg, 1.7 mmol, 60% dispersion in mineral oil) in DMF(10 ml). After stirring for a further 0.5 h, iodomethane (266 mg, 0.87mmol) was added. The mixture was stirred at room temperature for 72 hthen partitioned between water and ethyl acetate. The organic phase waswashed with water, brine, dried (Na₂SO₄) and the solvent removed invacuo. Purification by HPLC (Supercosil ABZ⁺, 5-95% acetonitrilecontaining 0.1% trifluoroacetic acid-water containing 0.1%trifluoroacetic acid) afforded the title compounds (structuresassignment based on nOe experiments):

-   1-[2-(6,7-Difluoro-1-methyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methyl-thiazol-4-yl]-methanone    (76 mg)

Mass spectrum (Electrospray LC/MS): Found 485 (MH⁺). C₂₅H₂₃F₃N₄OSrequires 484.

¹H NMR δ: 0.75-1.85 (6H, bm), 2.42 and 2.72 (3H, s), 0.85-3.15 (2H, bm),3.30 (1H, m), 3.42 (0.7H, m), 3.70 and 4.15 (3H, s), 4.25 (0.3H, m),4.75 (0.3H, m), 5.10 (0.7H, m), 7.00 (3H, m), 7.35 (3H, m).

-   1-[2-(4,5-Difluoro-1-methyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methyl-thiazol-4-yl]-methanone    (106 mg)

Mass spectrum (Electrospray LC/MS): Found 485 (MH⁺). C₂₅H₂₃F₃N₄OSrequires 484.

¹H NMR δ: 0.75-1.90 (6H, bm), 2.25 and 2.70 (3H, s), 2.9-3.2 (2H, bm),3.15-3.45 (1.7H, bm), 3.56 and 3.94 (3H, s), 4.25 (0.3H, m), 4.76 (0.3H,m), 5.09 (0.7H, m), 6.98 (3H, m), 7.08 (1H, m), 7.36 (2H, m).

EXAMPLE 76(RS)-2-(1-{1-[5-(4-Fluorophenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-ylmethyl)-benzofuran-3-carboxylicacid amide

To a solution of(RS)-2-(1-(2,2,2-trifluoro-ethanoyl)-piperidin-2-yl-methyl)-benzofuran-3-carbonitrile,D42 (480 mg, 1.4 mmol) in methanol (15 ml) and water (3 ml) was addedpotassium carbonate (700 mg, 4.9 mmol) and the mixture heated at refluxfor 1.25 h. The solvent was removed in vacuo and the residue waspartitioned between dichloromethane and water and basified to pH14. Theaqueous phase was re-extracted with dichloromethane (3×). The combinedorganics were dried (Na₂SO₄) and the solvent removed in vacuo to afforda solid (0.34 g, 99%). To a portion of this material (67 mg, 0.28 mmol)in dichloromethane was added5-(4-fluorophenyl)-2-methyl-thiazole-4-carboxylic acid (73 mg, 0.30mmol), EDC.HCl (60 mg, 0.30 mml) and 1-hydroxybenzotriazole (10 mg).After 16 h at room temperature the reaction mixture was washed withsaturated aqueous sodium hydrogen carbonate and the organic phaseapplied directly onto a pre-packed silica gel column. Elution with ethylacetate-methanol mixtures afforded the title compound as an amorphoussolid (8 mg, 6%).

Mass spectrum (Electrospray LC/MS): Found 478 (MH⁺). C₂₆H₂₄FN₃O₃Srequires 477.

EXAMPLE 77(RS)-2-(1-{1-[4-(4-Fluorophenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-benzofuran-3-carboxylicacid amide

The title compound (7 mg, 5%), was prepared as described for E76 from(RS)-2-(1-(2,2,2-trifluoro-ethanoyl)-piperidin-2-yl-methyl)-benzofuran-3-carbonitrile,D42 and 4-(4-fluorophenyl)-1-methyl-1H-pyrazole carboxylic acid (61 mg,0.3 mmol)

Mass spectrum (Electrospray LC/MS): Found 461 (MH⁺). C₂₆H₂₅FN₄O₃requires 460.

EXAMPLE 78(RS)-1-[3-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-morpholin-4-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (93 mg, 36%) was prepared from(4-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-morpholin-3-yl)-aceticacid, D45 according to the procedure described for Example 27.

Mass spectrum (Electrospray LC/MS): Found 473 (MH⁺). C₂₃H₁₉F₃N₄O₂Srequires 472.

EXAMPLE 79(RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-(2-furo[3,2-b]-pyridin-2-ylmethyl-piperidin-1-yl)methanone

The title compound was prepared using the method of Example 4, from5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (120 mg, 0.5mmol) and (RS)-2-piperidin-2-ylmethyl-furo[3,2-b]pyridine, D47 (108 mg,0.5 mmol), as a colourless solid (95 mg, 43%).

Mass spectrum (Electrospray LC/MS): Found 436 (MH⁺). C₂₄H₂₂FN₃O₂Srequires 435.

EXAMPLE 80(RS)-1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazole-3-yl)-(2-furo[3,2-b]pyridin-2-ylmethyl-piperidin-1-yl)methanone

The title compound was prepared using the method of Example 4, from4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (110 mg, 0.5mmol) and (RS)-2-Piperidin-2-ylmethyl-furo[3,2-b]pyridine, D47 (108 mg,0.5 mmol), as a colourless solid (130 mg, 62%).

Mass spectrum (Electrospray LC/MS): Found 419 (MH⁺). C₂₄H₂₃FN₄O₂requires 418.

EXAMPLE 81(RS)-1-[2-(3-Bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

To(RS)-2-(2-benzofuranylmethyl)-1-((5-(4-fluorophenyl)-2-methyl-thiazol-4-yl)-carbonyl)-piperidine,E1 (0.90 g, 2 mmol) in dry diethyl ether (10 ml) and dichloromethane (20ml) cooled to −12° C. under argon, was added drop-wise a solution ofbromine (0.36 g, 2 mmol) in dichloromethane (10 ml) over 0.5 h. Theresulting solution was warmed to ambient temperature over 1.5 h, thenstirred for a further 18 h. The reaction mixture was evaporated thenre-evaporated from dichloromethane (3×). The resulting amorphous solidwas chromatographed (silica gel with ethyl acetate-hexane mixtures) toafford the title compound as an amorphous solid (0.27 g, 25%).

Mass spectrum (Electrospray LC/MS) Found 513 (MH⁺). C₂₅H₂₂ ⁷⁹BrFN₂O₂Srequires 512.

EXAMPLE 82(RS)-2-(1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-ylmethyl)-benzofuran-3-carbonitrile

To(RS)-1-[2-(3-bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone,E81 (270 mg, 0.53 mmol) in N-methyl-pyrrolidinone (8 ml) was addedcopper(I)cyanide (96 mg, 1.06 mmol) and the mixture stirred under argonat reflux for 6 h. The reaction mixture was cooled, poured into water(80 ml) and ethyl acetate (50 ml) and then filtered through kieselguhr.The filtrate was separated and the aqueous phase extracted with ethylacetate (2×). The combined organics were washed with water (4×50 ml),dried and the solvent removed in vacuo. Chromatography (silica gel)afforded the title compound as a white amorphous solid (94 mg, 39%).

Mass spectrum (Electrospray LC/MS) Found 460 (MH⁺). C₂₆H₂₂FN₃O₂Srequires 459.

EXAMPLE 83(RS)-1-[2-(5-Fluorobenzofuran-2-ylmethyl)-4-methylpiperazin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone.hydrochloride

The title compound was prepared from(RS)-3-(5-fluorobenzofuran-2-ylmethyl)-1-methylpiperazine, D51 using themethod of Example 1.

Mass spectrum (Electrospray LC/MS): Found 468 (MH⁺). C₂₅H₂₃F₂O₂Srequires 467.

EXAMPLE 84(RS)-1-(2-Benzofuran-2-ylmethyl-4-methyl-piperazin-1-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl)]-methanone

The title compound (0.53 g, 32%) was obtained from(RS)-3-benzofuran-2-ylmethyl-1-methyl-piperazine, D56 (0.89 g, 3.8 mmol)using the method of Example 1.

Mass spectrum (Electrospray LC/MS): Found 450 (MH⁺). C₂₅H₂₄FN₃O₂Srequires 449.

EXAMPLE 85(RS)-1-(2-Benzofuran-2-ylmethyl-piperazin-1-yl)-1-[5-(4-fluorophenyl)-2-methyl-thiazol-4-yl]-methanone.hydrochloride

To(RS)-1-(2-benzofuran-2-ylmethyl-4-methyl-piperazin-1-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl)]-methanone,E84 (0.45 g, 1 mmol) in 1,2-dichloroethane (10 ml) under argon at 0° C.was added N,N-diisopropylethylamine (0.52 ml, 3 mmol) followed bydropwise addition of 1-chloroethylchloroformate (0.77 ml, 6 mmol) over1-2 min. After 5 min, the reaction mixture was warmed to ambienttemperature over 0.5 h, and then heated at 65° C. for 4.5 h. AdditionalN,N-diisopropylethylamine (0.52 ml, 3 mmol) was added and heatingcontinued for a further 2 h. The reaction was cooled and evaporated, andthe residue refluxed in methanol (25 ml) for 2.5 h. The cooled reactionwas evaporated and partitioned between dichloromethane (50 ml) andsaturated aqueous sodium bicarbonate (25 ml), aqueous phase extractedwith dichloromethane (2×25 ml). The combined organic extracts were dried(Na₂SO₄), evaporated and the residue chromatographed on silica geleluting with methanol ethyl acetate mixtures to afford the free-base ofthe title compound (0.23 g, 52%). A sample was converted to thehydrochloride salt by dissolving in methanol/dichloromethane andtreating with excess 1M HCl in diethyl ether. Removal of the solvent invacuo afforded the title compound as an amorphous solid.

Mass spectrum (Electrospray LC/MS): Found 458 (MNa⁺). C₂₄H₂₂FN₃O₂Srequires 435.

EXAMPLE 861-{(RS)-2-[(RS)-1-(5-Fluoro-benzofuranyl-2-yl)-1-hydroxy-methyl]-4-methyl-piperazin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (0.043 g, 59%) was obtained from(RS)-1-(5-fluoro-benzofuran-2-yl)-1-((RS)-4-methyl-piperazin-2-yl)-methanol,D57 and 5-(4-(fluorophenyl)-2-methyl-thiazole-4-carbonyl chloride (0.043g, 0.16 mmol) using the method of Example 1.

Mass spectrum (Electrospray LC/MS): Found 506 (MNa⁺). C₂₅H₂₃F₂N₃O₃Srequires 483.

EXAMPLE 871-{(RS)-2-[(RS)-1-(5-Fluoro-benzofuranyl-2-yl)-1-hydroxy-methyl]-4-methyl-piperazin-1-yl}-1-(2-trifluoromethoxy-phenyl)-methanone

The title compound (0.034 g, 50%) was obtained from(RS)-1-(5-fluoro-benzofuran-2-yl)-1-((RS)-4-methyl-piperizan-2-yl)-methanol,D57 and 2-(trifluoromethoxy)benzoyl chloride using the method of Example1.

Mass spectrum (Electrospray LC/MS): Found 453 (MH⁺). C₂₂H₂₀F₄N₂O₄requires 452.

EXAMPLE 88(RS)-1-[2-(1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-ylmethyl)-benzofuran-3-yl]-ethanone

The title compound (120 mg, 41%) was obtained from(RS)-1-[2-(3-bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone,E81 (320 mg, 0.62 mmol) using the method of Example 68.

Mass spectrum (Electrospray LC/MS): Found 477 (MH⁺). C₂₇H₂₅FN₂O₃Srequires 476.

EXAMPLE 89a AND EXAMPLE 89b(R)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoneand(S)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoneE35 (380 mg) was separated to give the title compounds (stereochemistrynot assigned) on a Chiralpak AD column (250 mm×19 mm i.d.; 10 micronparticle size); Mobile Phase: n-hexane, HiPerSiolv: ethanol, 99.7%v/v-100% v/v, Analar: triethylamine, Analar (90:10:0.25 v/v/v):pre-mixed: isocratic procedure; injecting at 2.5 ml at concentration of20 mg/ml racemate in ethanol, 99.7% v/v-100% v/v, Analar.

Faster eluting enantiomer (132 mg, >99.8% e.e.):

Mass spectrum (Electrospray LC/MS): Found 471 (MH⁺). C₂₄H₂₁F₃N₄OSrequires 470

Slower eluting enantiomer (173 mg, >99.8% e.e.):

Mass spectrum (Electrospray LC/MS): Found 471 (MH⁺). C₂₄H₂₁F₃N₄OSrequires 470

TABLE 5

Mass Spectrum (Electrospray Example Ar² Method LC/MS) 113

E2 Found MH⁺453. C₂₄H₂₂F₂N₄OS requires 452. 114

E2 Found MH⁺436. C₂₄H₂₃F₂N₅O requires 435. 115

E2 Found MH⁺422. C₂₃H₂₁F₂N₅O requires 421. 116

E2 Found MH⁺436. C₂₄H₂₃F₂N₅O requires 435. 117

E2 Found MH⁺382. C₂₂H₂₄FN₃O₂ requires 381. 118

E4 Found M-1 467. C₂₄H₂₂F₂N₄O₂S requires 468. (API LC/MS)

The compounds of Examples 113-118 were prepared from the appropriatecarboxylic acid and(RS)-4-fluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole, D58 using aprocedure similar to that described in Example 2 or Example 4.

EXAMPLE 119(RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{2-[4-(1-hydroxy-ethyl)-1H-benzoimidazol-2-ylmethyl]-piperidin-1-yl}-methanone

Sodium borohydride (145 mg) was added portionwise over 2 min. to acooled (0-10° C.) solution of(RS)-1-[2-(4-acetyl-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone,E68 (365 mg) in methanol (10 ml). After stirring for a further 2.5 h atroom temperature, water (100 ml) was added and the mixture was extractedwith dichloromethane (2×). The combined organics were dried (Na₂SO₄),evaporated and the residue chromatographed (silica gel, 0-100% ethylacetate-hexane then 2-10% methanol-ethyl acetate) to afford the titlecompound as a solid (320 mg).

Mass spectrum (Electrospray LC/MS): Found 479 (MH⁺). C₂₆H₂₇FN₄O₂Srequires 478.

EXAMPLE 120(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-[5-(4-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (100 mg) was prepared from(RS)-2-(2-benzofuranylmethyl)piperidine, D3 (64 mg) and5-(4-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid (76 mg) by aprocedure similar to that described for Example 2.

Mass spectrum (API LC/MS): Found 451 (MH⁺). C₂₅H₂₃ ³⁵ClN₂O₂S requires450.

EXAMPLE 121(RS)-1-[2-(3-Chloro-furo[3,2-b]pyridin-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

A solution of chlorine (28 mg) in dichloromethane (3 ml) was added to acooled (−12° C.) solution(RS)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-(2-furo[3,2-b]-pyridin-2-ylmethyl-piperidin-1-yl)methanone,E79 (170 mg) in dichloromethane (4 ml). After stirring at −12° C. for0.5 h the reaction mixture was stirred at room temperature for 16 h thenthe solution was washed with saturated aqueous NaHCO₃, dried (Na₂SO₄)and the solvent removed in vacuo. Chromatography (silica gel, 0-100%ethyl acetate-hexane then 0-10% methanol-ethyl acetate) afforded thetitle compound (24 mg).

Mass spectrum (Electrospray LC/MS): Found 470 (MH⁺). C₂₄H₂₁ ³⁵ClFN₃O₂Srequires 469.

EXAMPLE 122(RS)-1-[2-(5,6-Difluoro-1-methyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone

The title compound (15 mg) was prepared from5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazole-4-carboxylic acid (84 mg)and (RS)-5,6-difluoro-1-methyl-2-piperidin-2-ylmethyl-1H-benzoimidazole,D61 (86 mg) by a procedure similar to that described for Example 4.

Mass spectrum (Electrospray LC/MS): Found 501 (MH⁺). C₂₅H₂₃F₃N₄O₂Srequires 500.

EXAMPLE 123(RS)-1-[2-(5-Chloro-benzofuran-2-ylmethyl)-4-methyl-piperazin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (135 mg) was prepared from5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (211 mg) and3-(5-Chloro-benzofuran-2-ylmethyl)-1-methyl-piperazine, D63 (200 mg) bya procedure similar to that described for Example 1.

Mass spectrum (API⁺LC/MS): Found 484 (MH⁺). C₂₅H₂₃ ³⁵ClFN₃O₂S requires483

EXAMPLE 124(RS)-1-[2-(5-Chloro-benzofuran-2-ylmethyl)-piperazin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound was prepared from1-[2-(5-chloro-benzofuran-2-ylmethyl)-4-methyl-piperazin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone,E123 (95 mg) by a procedure similar to that described for Example 85.

Purification by HPLC (Supercosil ABZ⁺, 5-95% acetonitrile containing0.1% trifluoroacetic acid-water containing 0.1% trifluoroacetic acid)afforded the title compound (5 mg) as the TFA salt.

Mass spectrum (Electrospray LC/MS): Found 470 (MH⁺). C₂₄H₂₁ ³⁵ClFN₃O₂Srequires 469.

EXAMPLE 125(RS)-1-[2-(5,7-Dichloro-benzofuran-2-ylmethyl)-4-methyl-piperazin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (80 mg) was prepared from5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (498 mg) and(RS)-3-(5,7-dichloro-benzofuran-2-ylmethyl)-1-methyl-piperazine, D65(530 mg) by a procedure similar to that described for Example 1.

Mass spectrum (API⁺LC/MS): Found 518 (MH⁺). C₂₅H₂₂ ³⁵Cl₂FN₃O₂S requires517.

EXAMPLE 126(RS)-1-[2-(5,7-Dichloro-benzofuran-2-ylmethyl)-piperazin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound was prepared from(RS)-1-[2-(5,7-dichloro-benzofuran-2-ylmethyl)-4-methyl-piperazin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoneE125 (72 mg) by a procedure similar to that described for Example 85.Purification by HPLC (Supercosil ABZ⁺, 5-95% acetonitrile containing0.1% trifluoroacetic acid-water containing 0.1% trifluoroacetic acid)afforded the title compound (6 mg) as the TFA salt.

Mass spectrum (Electrospray LC/MS): Found 504 (MH⁺). C₂₄H₂₀ ³⁵Cl₂FN₃O₂Srequires 503.

EXAMPLE 127(RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(1H-indol-2-ylmethyl)-piperidin-1-yl]-methanone

(RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-2-ylmethyl]-piperidin-1-yl}-methanone(130 mg) was prepared from(RS)-2-piperidin-2-ylmethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole,D68 (520 mg) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonylchloride (512 mg) according to a procedure similar to that forExample 1. A stirring solution of the above amide (125 mg) in dry THF (5ml) was treated with a solution of tetrabutylammonium fluoride (2.2mmol) in THF (5 ml). Once tlc indicated the reaction had gone tocompletion, the reaction mixture was poured into water and the productextracted with ethyl acetate. The combined organics were washed withbrine, dried (Na₂SO₄) and the solvent removed in vacuo. Chromatography(silica gel, 0-100% pentane-ethyl acetate followed by preparative tlc,40% ethyl acetate-pentane) afforded the title compound as a white solid(2.5 mg).

Mass spectrum (Electrospray LC/MS): Found 434 (MH⁺). C₂₅H₂₄FN₃OSrequires 433.

EXAMPLE 128(RS)-5-[1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-methanoyl]-4H-benzo[1,4]oxazin-3-one

The title compound (65 mg) was prepared from(RS)-2-(2-benzofuranylmethyl)piperidine, D3 (65 mg) and3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-5-carboxylic acid (39 mg) by aprocedure similar to that for Example 2.

Mass spectrum (Electrospray LC/MS): Found 391 (MH⁺). C₂₃H₂₂N₂O₄ requires390.

EXAMPLE 129(RS)-1-[2-(5-Bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (490 mg) was prepared from5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (488 mg) and(RS)-2-(5-bromo-benzofuran-2-ylmethyl)-piperidine, D70 (530 mg) by aprocedure similar to that described for Example 1.

Mass spectrum (Electrospray LC/MS): Found 513 (MH⁺). C₂₅H₂₂ ⁷⁹BrFN₂O₂Srequires 512.

EXAMPLE 130(RS)-1-[2-(5-Cyano-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (19 mg) was prepared from(RS)-1-[2-(5-bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone,E129 (420 mg) and copper(I)cyanide according to a procedure similar tothat described for Example 67.

Mass spectrum (API⁺LC/MS): Found 460 (MH⁺). C₂₆H₂₂FN₃O₂S requires 459.

EXAMPLE 131(RS)-1-[2-(4-Bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (0.45 g) was prepared from5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (0.89 g) and2-(4-bromo-benzofuran-2-ylmethyl)-piperidine, D72 (0.88 g) by aprocedure similar to that described for Example 1.

Mass spectrum (Electrospray LC/MS): Found 513 (MH⁺). C₂₅H₂₂ ⁷⁹BrFN₂O₂Srequires 512.

EXAMPLE 132(RS)-1-[2-(4-Cyano-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (80 mg) was prepared from(RS)-1-[2-(4-bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone,E131 (400 mg) and copper(I)cyanide according to a procedure similar tothat described for Example 67.

Mass spectrum (Electrospray LC/MS): Found 460 (MH⁺). C₂₆H₂₂FN₃O₂Srequires 459.

EXAMPLE 133(RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(3-methyl-benzofuran-2-ylmethyl)-piperidin-1-yl]-methanone

The title compound (18 mg) was prepared from(RS)-2-(3-methyl-benzofuran-2-ylmethyl)-piperidine, D74 (92 mg) and5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (190 mg)according to a procedure similar to that described for Example 4.

Mass spectrum (API LC/MS): Found 449 (MH⁺). C₂₆H₂₅FN₂O₂S requires 448.

EXAMPLE 134(RS)-1-[2-(4-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (60 mg) was prepared from(RS)-2-(4-fluoro-benzofuran-2-ylmethyl)-piperidine, D76 (157 mg) and5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (160 mg)according to a procedure similar to that described for Example 4.

Mass spectrum (API LC/MS): Found 453 (MH⁺). C₂₅H₂₂F₂N₂O₂S requires 452.

EXAMPLE 135(RS)-1-[2-(4-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone

The title compound (45 mg) was prepared from(RS)-2-(4-fluoro-benzofuran-2-ylmethyl)-piperidine, D76 (157 mg) and4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (160 mg)according to a procedure similar to that described for Example 4.

Mass spectrum (API LC/MS): Found 436 (MH⁺). C₂₅H₂₃F₂N₃O₂ requires 435.

EXAMPLE 136(RS)-1-[2-(4,6-Dichloro-benzofuran-2-ylmethyl)-4-methyl-piperazin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (107 mg) was prepared from5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (241 mg) and3-(4,6-dichloro-benzofuran-2-ylmethyl)-1-methyl-piperazine, D78 (263 mg)by a procedure similar to that described for Example 1.

Mass spectrum (Electrospray LC/MS): Found 518 (MH⁺). C₂₅H₂₂ ³⁵Cl₂FN₃O₂Srequires 517.

EXAMPLE 137(RS)-1-[2-(4,6-Dichloro-benzofuran-2-ylmethyl)-piperazin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound was prepared from(RS)-1-[2-(4,6-dichloro-benzofuran-2-ylmethyl)-4-methyl-piperazin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone,E136 (87 mg) by a procedure similar to that described for Example 85.

Purification by HPLC (Supercosil ABZ⁺, 5-95% acetonitrile containing0.1% trifluoroacetic acid-water containing 0.1% trifluoroacetic acid)afforded the title compound (mg) as the TFA salt.

Mass spectrum (Electrospray LC/MS): Found 504 (MH⁺). C₂₄H₂₀ ³⁵Cl₂FN₃O₂Srequires 503.

EXAMPLE 138(RS)-1-(2-Benzofuran-2-ylmethyl-pyrrolidin-1-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (45 mg) was prepared from(RS)-2-benzofuran-2-ylmethyl-pyrrolidine D81 (114 mg) and5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (147 mg)according to a procedure similar to that described for Example 4.

Mass spectrum (Electrospray LC/MS): Found 421 (MH⁺). C₂₄H₂₁FN₂O₂Srequires 420.

EXAMPLE 139(RS)-1-(2-Benzofuran-2-ylmethyl-pyrrolidin-1-yl)-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone

The title compound (29 mg) was prepared from(RS)-2-benzofuran-2-ylmethyl-pyrrolidine D81 (114 mg) and4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (137 mg)according to a procedure similar to that described for Example 4.

Mass spectrum (Electrospray LC/MS): Found 404 (MH⁺). C₂₄H₂₂FN₃O₂requires 403.

EXAMPLE 140(RS)-1-(2-Benzo[b]thiophen-2-ylmethyl-piperidin-1-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (40 mg) was prepared from2-benzo[b]thiophen-2-ylmethyl-piperidine

D83 (133 mg) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid(136 mg) according to a procedure similar to that described for Example4.

Mass spectrum (Electrospray LC/MS): Found 451 (MH⁺). C₂₅H₂₃FN₂OS₂requires 450.

EXAMPLE 141(RS)-1-(2-Benzo[b]thiophen-2-ylmethyl-piperidin-1-yl)-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone

The title compound (6 mg) was prepared from2-benzo[b]thiophen-2-ylmethyl-piperidine

D83 (133 mg) and 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid (140 mg) according to a procedure similar to that described forExample 4.

Mass spectrum (Electrospray LC/MS): Found 434 (MH⁺). C₂₅H₂₄FN₃OSrequires 433.

EXAMPLE 142(RS)-1-(2-Benzo[b]thiophen-2-ylmethyl-piperidin-1-yl)-1-quinolin-8-yl-methanone

The title compound (4 mg) was prepared from2-benzo[b]thiophen-2-ylmethyl-piperidine D83 (133 mg) and 8-quinolinecarboxylic acid (109 mg) according to a procedure similar to thatdescribed for Example 4.

Mass spectrum (Electrospray LC/MS): Found 387 (MH⁺). C₂₄H₂₂N₂OS requires386

EXAMPLE 143(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-(2-methyl-5-phenyl-thiazol-4-yl)-methanone

The title compound (90 mg) was prepared from(RS)-2-(2-benzofuranylmethyl)piperidine, D3 (100 mg) and5-phenyl-2-methyl-thiazole-4-carbonyl chloride (122 mg) according to aprocedure similar to that for Example 1.

Mass spectrum (Electrospray LC/MS): Found 417 (MH⁺). C₂₅H₂₄N₂O₂Srequires 416.

EXAMPLE 1441-[(S)-2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-pyrrolidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone

The title compound (65 mg) was prepared from5,6-difluoro-2-(S)-1-pyrrolidin-2-ylmethyl-1H-benzoimidazole, D27 (153mg) and 5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazole-4-carboxylic acid(205 mg) according to a procedure similar to that for Example 4.

Mass spectrum (Electrospray LC/MS): Found 473 (MH⁺). C₂₃H₁₉F₃N₄O₂Srequires 472.

EXAMPLE 145(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone

The title compound (33 mg) was prepared from(RS)-2-(2-benzofuranylmethyl)piperidine, D3 (108 mg) and2-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoic acid (102 mg) according to aprocedure similar to that for Example 2.

Mass spectrum (Electrospray LC/MS): Found 402 (MH⁺). C₂₄H₂₃N₃O₃ requires401.

EXAMPLE 146a AND EXAMPLE 146b(R)-1-[2-(4,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoneand(S)-1-[2-(4,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone(enantiomers of Example 32)

(RS)-1-[2-(4,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone,E32 was separated to give the title compounds (stereochemistry notassigned) using the following procedures:

Analytical separation: 10 uL of diluted sample (compound in methanol)was separated on a 4.6×250 mm, 10 micron, analytical ChiralCel ODcolumn. A Berger Analytical SFC (Super Critical Fluid) instrument wasused with system parameters as follows: mobile phase=90% CO₂:10% organicmodifier, organic modifier=90% methanol:10% chloroform v/v, 3000 psi, 2mL/min, 40 C λ=254 nm

The enantiomers eluted at 6.4 min. and 8.1 min.

Preparative separation: Scale-up was preformed on a Prochrom Super C.20instrument. The instrument parameters were as follows: 40 C, 21 MPa, 40g/min CO2+4.5 ml/min organic modifier (as above), λ=300 nm, ChiralCel OD20×250 mm, 10 micron column. 30 mg of racemate was introduced per cycle.Sample concentration=875 mg/13 ml solvent (sample solvent=5 mlchloroform and 8 mL methanol). Cycle time (run time)=17 minutes. Theenantiomers eluted at 10.2 and 13.6 min. Elution times measured at peakmaxima.

It is understood that the present invention covers all combinations ofparticular and preferred groups described herein above.

Determination of Orexin-1 Receptor Antagonist Activity

The orexin-1 receptor antagonist activity of the compounds of formula(I) was determined in accordance with the following experimental method.

Experimental Method

CHO-DG44 cells expressing the human orexin-1 receptor were grown in cellmedium (MEM medium with Earl's salts) containing 2 mM L-Glutamine, 0.4mg/mL G418 Sulphate from GIBCO BRL and 10% heat inactivated fetal calfserum from Gibco BRL. The cells were seeded at 20,000 cells/100 μl/wellinto 96-well black clear bottom sterile plates from Costar which hadbeen pre-coated with 10 μg/well of poly-L-lysine from SIGMA. The seededplates were incubated overnight at 37 C in 5% CO₂.

Agonists were prepared as 1 mM stocks in water:DMSO (1:1). EC50 values(the concentration required to produce 50% maximal response) wereestimated using 11× half log unit dilutions (Biomek 2000, Beckman) inTyrode's buffer containing probenecid (10 mM HEPES with 145 mM NaCl, 10mM glucose, 2.5 mM KCl, 1.5 mM CaCl₂, 1.2 mM MgCl₂ and 2.5 mMprobenecid; pH7.4). Antagonists were prepared as 10 mM stocks in DMSO(100%). Antagonist IC50 values (the concentration of compound needed toinhibit 50% of the agonist response) were determined against 3.0 nMhuman orexin-A using 11× half log unit dilutions in Tyrode's buffercontaining 10% DMSO and probenecid.

On the day of assay 50 μl of cell medium containing probenecid (Sigma)and Fluo3AM (Texas Fluorescence Laboratories) was added (Quadra, Tomtec)to each well to give final concentrations of 2.5 mM and 4 μM,respectively. The 96-well plates were incubated for 60 min at 37 C in 5%CO2. The loading solution containing dye was then aspirated and cellswere washed with 4×150 μl Tyrode's buffer containing probenecid and 0.1%gelatin (Denley Cell Wash). The volume of buffer left in each well was125 μl. Antagonist or buffer (25 μl) was added (Quadra) the cell platesgently shaken and incubated at 37 C in 5% CO₂ for 30 minutes. Cellplates were then transferred to the Fluorescent Imaging Plate Reader(FLIPR, Molecular Devices) instrument. Prior to drug addition a singleimage of the cell plate was taken (signal test), to evaluate dye loadingconsistency. The run protocol used 60 images taken at 1 second intervalsfollowed by a further 24 images at 5 second intervals. Agonists wereadded (by the FLIPR) after 20 seconds (during continuous reading). Fromeach well, peak fluorescence was determined over the whole assay periodand the mean of readings 1-19 inclusive was subtracted from this figure.The peak increase in fluorescence was plotted against compoundconcentration and iteratively curve fitted using a four parameterlogistic fit (as described by Bowen and Jerman, TiPS, 1995, 16, 413-417)to generate a concentration effect value. Antagonist Kb values werecalculated using the equation:Kb=IC50/(1+([3/EC50])

where EC50 was the potency of human orexin-A determined in the assay (innM terms) and IC50 is expressed in molar terms.

Compounds of Examples tested according to this method had pKb values>7.0to 9.4 at the human cloned orexin-1 receptor.

The orexin-2 receptor antagonist activity of the compounds of formula(I) was determined in accordance with the following experimental method.

Experimental Method

CHO-DG44 cells expressing the human orexin-2 receptor were grown in cellmedium (MEM medium with Earl's salts) containing 2 mM L-Glutamine, 0.4mg/mL G418 Sulphate from GIBCO BRL and 10% heat inactivated fetal calfserum from Gibco BRL. The cells were seeded at 20,000 cells/100 μl/wellinto 96-well black clear bottom sterile plates from Costar which hadbeen pre-coated with 10 μg/well of poly-L-lysine from SIGMA. The seededplates were incubated overnight at 37 C in 5% CO₂.

Agonists were prepared as 1 mM stocks in water:DMSO (1:1). EC50 values(the concentration required to produce 50% maximal response) wereestimated using 11× half log unit dilutions (Biomek 2000, Beckman) inTyrode's buffer containing probenecid (10 mM HEPES with 145 mM NaCl, 10mM glucose, 2.5 mM KCl, 1.5 mM CaCl₂, 1.2 mM MgCl₂ and 2.5 mMprobenecid; pH7.4). Antagonists were prepared as 10 mM stocks in DMSO(100%). Antagonist IC50 values (the concentration of compound needed toinhibit 50% of the agonist response) were determined against 10.0 nMhuman orexin-A using 11× half log unit dilutions in Tyrode's buffercontaining 10% DMSO and probenecid.

On the day of assay 50 μl of cell medium containing probenecid (Sigma)and Fluo3AM (Texas Fluorescence Laboratories) was added (Quadra, Tomtec)to each well to give final concentrations of 2.5 mM and 4 μM,respectively. The 96-well plates were incubated for 60 min at 37 C in 5%CO₂. The loading solution containing dye was then aspirated and cellswere washed with 4×150 μl Tyrode's buffer containing probenecid and 0.1%gelatin (Denley Cell Wash). The volume of buffer left in each well was125 μl. Antagonist or buffer (25 μl) was added (Quadra) the cell platesgently shaken and incubated at 37 C in 5% CO₂ for 30 min. Cell plateswere then transferred to the Fluorescent Imaging Plate Reader (FLIPR,Molecular Devices) instrument. Prior to drug addition a single image ofthe cell plate was taken (signal test), to evaluate dye loadingconsistency. The run protocol used 60 images taken at 1 second intervalsfollowed by a further 24 images at 5 second intervals. Agonists wereadded (by the FLIPR) after 20 sec (during continuous reading). From eachwell, peak fluorescence was determined over the whole assay period andthe mean of readings 1-19 inclusive was subtracted from this figure. Thepeak increase in fluorescence was plotted against compound concentrationand iteratively curve fitted using a four parameter logistic fit (asdescribed by Bowen and Jerman, TiPS, 1995, 16, 413-417) to generate aconcentration effect value. Antagonist Kb values were calculated usingthe equation:Kb=IC50/(1+([3/EC50])where EC50 was the potency of human orexin-A determined in the assay (innM terms) and IC50 is expressed in molar terms.

Compounds of Examples tested according to this method had pKb values inthe range 6.5-8.4 at the human cloned orexin-2 receptor.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation the following claims:

1. A compound of formula (I):

wherein X represents CH₂; Y represents CH₂, CH(OH), or CH₂CH(OH); Het isan optionally substituted benzofuranyl; Ar² represents an optionallysubstituted isoquinolinyl group; wherein said optionally substituted Hetor Ar² groups are optionally substituted by halogen, hydroxy, oxo,cyano, nitro, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, hydroxy(C₁₋₄alkyl,hydroxy(C₁₋₄)alkoxy, halo(C₁₋₄)alkyl, halo(C₁₋₄)alkoxy,aryl(C₁₋₄)alkoxy, (C₁₋₄)alkylthio, hydroxy(C₁₋₄)alkyl,(C₁₋₄)alkoxy(C₁₋₄)alkyl, (C₃₋₆)cycloalkyl(C₁₋₄)alkoxy, (C₁₋₄)alkanoyl,(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylsulfonyl, (C₁₋₄)alkylsulfonyloxy,(C₁₋₄)alkylsulfonyl(C₁₋₄)alkyl, arylsulfonyl, arylsulfonyloxy,arylsulfonyl(C₁₋₄)alkyl, (C₁₋₄)alkylsulfonamido, (C₁₋₄)alkylamido,(C₁₋₄)alkylsulfonamido(C₁₋₄)alkyl, (C₁₋₄)alkylamido(C₁₋₄)alkyl,arylsulfonamido, arylcarboxamido, arylsulfonamido(C₁₋₄)alkyl,arylcarboxamido(C₁₋₄)alkyl, aroyl, aroyl(C₁₋₄)alkyl, aryl(C₁₋₄)alkanoyl,(C₁₋₄)acyl, aryl, aryl(C₁₋₄)alkyl, (C₁₋₄)alkylamino(C₁₋₄)alkyl, orR^(a)R^(b)N—, R^(a)OCO(CH₂)_(r), R^(a)CON(R^(a))(CH₂)_(r),R^(a)R^(b)NCO(CH₂)_(r), R^(a)R^(b)NSO₂(CH₂)_(r),R^(a)SO₂NR^(b)(CH₂)_(r), R^(a)R^(b)N(CH₂)_(n)—, R^(a)R^(b)N(CH₂)_(n)O—,wherein r represents zero or an integer from 1 to 4, n represents aninteger from 1 to 4, and each of R^(a) and R^(b) independentlyrepresents a hydrogen atom or a (C₁₋₄)alkyl group, or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1 wherein Ar²is optionally substituted by (C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl,R^(a)R^(b)N, (C₁₋₄)alkoxy, R^(a)R^(b)N(CH₂)n, (C₁₋₄)acyl, and(C₁₋₄)alkylamido.
 3. A compound according to claim 1 wherein Yrepresents CH₂.
 4. A compound:(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-isoquinolin-8-yl-methanone;(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-isoquinolin-5-yl-methanone;or a pharmaceutically acceptable salt of any one thereof.
 5. Apharmaceutical composition comprising a therapeutically effective amountof the compound according to claim 1, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.
 6. A method oftreating a disease or disorder where an antagonist of a human orexinreceptor is required, which comprises administering to a subject in needthereof an effective amount of the compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein said disease ordisorder is selected from obesity and obesity associated with Type IIdiabetes.
 7. A method of treating insomnia which comprises administeringto a subject in need thereof an effective amount of the compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof.